Publications by authors named "Hiroshi Yamazaki"

560 Publications

Preface.

Authors:
Hiroshi Yamazaki

Adv Pharmacol 2022 ;95:xiii-xiv

Showa Pharmaceutical University, Tokyo, Japan.

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http://dx.doi.org/10.1016/S1054-3589(22)00070-9DOI Listing
August 2022

Polymorphic cytochromes P450 in non-human primates.

Adv Pharmacol 2022 10;95:329-364. Epub 2022 Jun 10.

Showa Pharmaceutical University, Machida, Tokyo, Japan.

Cynomolgus macaques (Macaca fascicularis, an Old World monkey) are widely used in drug development because of their genetic and physiological similarities to humans, and this trend has continued with the use of common marmosets (Callithrix jacchus, a New World monkey). Information on the major drug-metabolizing cytochrome P450 (CYP, P450) enzymes of these primate species indicates that multiple forms of their P450 enzymes have generally similar substrate selectivities to those of human P450 enzymes; however, some differences in isoform, activity, and substrate specificity account for limited species differences in drug oxidative metabolism. This review provides information on the P450 enzymes of cynomolgus macaques and marmosets, including cDNA, tissue expression, substrate specificity, and genetic variants, along with age differences and induction. Typical examples of important P450s to be considered in drug metabolism studies include cynomolgus CYP2C19, which is expressed abundantly in liver and metabolizes numerous drugs. Moreover, genetic variants of cynomolgus CYP2C19 affect the individual pharmacokinetic data of drugs such as R-warfarin. These findings provide a foundation for understanding each P450 enzyme and the individual pharmacokinetic and toxicological results in cynomolgus macaques and marmosets as preclinical models. In addition, the effects of induction on some drug clearances mediated by P450 enzymes are also described. In summary, this review describes genetic and acquired individual differences in cynomolgus and marmoset P450 enzymes involved in drug oxidation that may be associated with pharmacological and/or toxicological effects.
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http://dx.doi.org/10.1016/bs.apha.2022.05.005DOI Listing
August 2022

Cytochrome P450s in chimeric mice with humanized liver.

Adv Pharmacol 2022 23;95:307-328. Epub 2022 Jul 23.

Showa Pharmaceutical University, Machida, Tokyo, Japan.

Chimeric mice with humanized livers (humanized liver mice) are attractive experimental animal models for drug metabolism and pharmacokinetic studies. The "humanized liver" is a mature and functional liver with zonal position-specific expressions of human cytochrome P450 (P450) enzymes and a global gene expression pattern consistent with that of the mature human liver. Most P450-dependent drug oxidation activities were comparable between microsomes from livers of human and humanized liver mice based on similar expression levels of human P450 enzymes; however, some differences were observed between the two species, including considerable variations in activities of bufuralol 1'-hydroxylation and propafenone 4'-hydroxylation. Human disproportionate and/or unique metabolites of P450 substrate drugs were produced in humanized liver mice. Plasma concentration profiles of typical P450 substrate drugs in humans could be extrapolated from the corresponding data in humanized liver mice using simplified physiologically based pharmacokinetic modeling. Drug-drug interaction-mediated hepatic human CYP3A/2C induction by rifampicin (a human pregnane X receptor agonist) was observed in humanized liver mice. The major role of human CYP2C9 in in vivo diclofenac 4'-hydroxylation were determined using human CYP2C9-inactivated chimeric mice using a mechanism-based inhibitor, tienilic acid. Overall, based on the functional characteristics of hepatic human P450 enzymes, humanized liver mice are valuable experimental animals for studying metabolite profiling, pharmacokinetics, and drug interactions.
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http://dx.doi.org/10.1016/bs.apha.2022.05.004DOI Listing
August 2022

A multicenter study to investigate the positive rate of SARS-CoV-2 in middle ear and mastoid specimens from otologic surgery patients.

Auris Nasus Larynx 2022 Jul 29. Epub 2022 Jul 29.

Department of Otolaryngology, Kobe City Medical Center General Hospital, Kobe, Japan.

Objective: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus, causes coronavirus disease 2019 (COVID-19). Otologic surgeries with drilling by powered instruments induce significant aerosols, which may induce SARS-CoV-2 transmission to medical staff if SARS-CoV-2 exists in the middle ear and mastoid cavity. During a COVID-19 pandemic, therefore, confirming a negative COVID-19 test prior to otologic surgery is recommended. However, previous coronavirus studies demonstrated that coronavirus was detected in the middle ear in some patients even though the polymerase chain reaction (PCR) test using their nasopharyngeal swab was negative. This study aimed to elucidate the probability of a positive SARS-CoV-2 PCR test in the middle ear or mastoid specimens from otologic surgery patients in whom SARS-CoV-2 was not detected by preoperative PCR test using a nasopharyngeal swab.

Methods: We conducted a prospective, multicenter clinical study. Between April 2020 and December 2021, during the COVID-19 pandemic, 251 ears of the 228 participants who underwent otologic surgery were included in this study. All participants had no symptoms suggesting COVID-19 or close contact with a confirmed COVID-19 patient two weeks prior to the surgery. They were also negative in the SARS-CoV-2 PCR tests using a nasopharyngeal swab before surgery. We collected mucosa, granulation, bone dust with mucosa or fluid from the middle ear or mastoid for the SARS-CoV-2 PCR tests during each otologic surgery.

Results: The median age of the participants at surgery was 31.5 years old. Mastoidectomy using a powered instrument was conducted in 180 of 251 otologic surgeries (71.8%). According to intraoperative findings, active inflammation in the middle ear or mastoid cavities was evident in 20 otologic surgeries (8.0%), while minor inflammation was observed in 77 (30.7%). All SARS-CoV-2 PCR tests of otologic specimens showed a negative result. No patient suffered from COVID-19 within two months after otologic surgery. Furthermore, no hospital-acquired infections associated with otologic surgery occurred in our institutions CONCLUSIONS: Our results showed that PCR testing did not detect SARS-CoV-2 in middle ear and mastoid specimens, suggesting that the risk of transmission of SARS-CoV-2 is not high in otologic surgeries even using powered instruments when both clinical and laboratory tests are confirmed to be negative for COVID-19.
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http://dx.doi.org/10.1016/j.anl.2022.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334977PMC
July 2022

High Deep Femoral Artery Bifurcation Can Disturb Safe Femoral Venous Access: CT Assessment in Patients Who Underwent Femoral Venous Access Under Doppler Ultrasound Guidance.

Interv Radiol (Higashimatsuyama) 2021 Jul 1;6(2):29-36. Epub 2021 Jul 1.

Department of Diagnostic Imaging and Nuclear Medicine, Tokyo Women's Medical University Hospital, Japan.

Purpose: To retrospectively evaluate the variations of deep femoral artery (DFA) bifurcation on computed tomography (CT) and technical success in femoral venous access.

Materials And Methods: CT images of 353 patients who underwent adrenal venous sampling were evaluated. Height with relation to the inferior border of the femoral head and direction of DFA bifurcations were classified as follows: type L, low bifurcation; type H1, high lateral bifurcation; type H2, high posterior to posterolateral bifurcation; type H3, high posteromedial bifurcation; and type H4, high medial bifurcation crossing in front of the femoral vein. Technical success and complications during femoral venous access were also evaluated.

Results: The frequencies of types L, H1, H2, H3, and H4 were 82.7%, 9.1%, 6.9%, 0.4%, and 0.9%, respectively. In 92.2% of type H1 and 69.4% of type H2, the superior femoral artery displaced medially by the high DFA partially overlapped the femoral vein. Upon the inclusions of H3 and H4, in 14.4% of cases, the high DFAs could obstruct the access route to the femoral vein. Using Doppler ultrasound guidance, no significant differences were observed in the rates of success for puncture in the first attempt (84.5% vs. 75.4%, p = 0.122) and accidental arterial puncture (1.0% vs. 0%, p = 1.00) between low and high DFA bifurcations, respectively.

Conclusions: High DFA bifurcation is observed in 17.3% of patients and could obstruct the access route to the femoral vein. This can be evaluated using Doppler ultrasound guidance to avoid accidental arterial puncture during femoral venous access.
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http://dx.doi.org/10.22575/interventionalradiology.2021-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327428PMC
July 2021

Further survey of genetic variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found in an updated database of genome resources and identified by phenotyping for trimethylaminuria.

Drug Metab Pharmacokinet 2022 Jun 24;46:100465. Epub 2022 Jun 24.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan. Electronic address:

The number of single-nucleotide substitutions of human flavin-containing monooxygenase 3 (FMO3) recorded in mega-databases is increasing. Moreover, phenotype-gene analyses have revealed impaired FMO3 variants associated with the metabolic disorder trimethylaminuria. In this study, four novel amino-acid substituted FMO3 variants, namely p.(Gly191Asp), p.(Glu414Gln), p.(Phe510Ser), and p.(Val530CysfsTer1), were identified in the whole-genome sequences in the Japanese population reference panel (8.3K JPN) of the Tohoku Medical Megabank Organization. Additionally, four variants, namely p.(Ile369Thr), p.(Phe463Val), p.(Arg500Gln), and p.(Ala526Thr) FMO3, were found in the 8.3K JPN database but were already recorded in the National Center for Biotechnology Information database. Novel FMO3 variants p.[(Met1Leu)] and p.[(Trp231Ter)] were also identified in phenotype-gene analyses of 290 unrelated subjects with self-reported malodor. Among the eight recombinant FMO3 variants tested (except for p.[(Met1Leu)] and p.[(Trp231Ter)]), Arg500Gln and Gly191Asp FMO3, respectively, had lower and much lower capacities for trimethylamine and/or benzydamine N-oxygenation activities than wild-type FMO3. Because another FMO3 mutation p.[(Gly191Cys)] with diminished recombinant protein activity was previously detected in two independent probands, Gly191 would appear to be important for FMO3 catalytic function. Analysis of whole-genome sequence data and trimethylaminuria phenotypes revealed missense FMO3 variants that severely impaired FMO3-mediated N-oxygenations in Japanese subjects that could be susceptible to low drug clearances.
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http://dx.doi.org/10.1016/j.dmpk.2022.100465DOI Listing
June 2022

Plasma and synovial fluid concentrations of linezolid in patients with knee osteoarthritis infected with Staphylococcus aureus.

J Pharm Health Care Sci 2022 Jul 1;8(1):16. Epub 2022 Jul 1.

Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan.

Background: Linezolid is a new oxazolidinone antibiotic used for infections caused by methicillin-resistant Staphylococcus and other species.

Case Presentation: Two cases of knee osteoarthritis with acute infection were successfully treated using linezolid. The plasma and synovial fluid concentrations of linezolid in two patients [women aged 69 and 73 years (cases 1 and 2)] with knee osteoarthritis infected with Staphylococcus aureus were measured after they were administered 600 mg twice daily by intravenous infusion. The plasma linezolid concentrations during knee surgery in case 1 at day 5 and in case 2 at day 2 were 19.6 and 15.6 μg/mL, respectively. The synovial fluid concentrations of linezolid in samples taken during surgery in case 1 and case 2 were 14.9 and 17.0 μg/mL, respectively; these values corresponded to ratios of synovial fluid/plasma of 76 and 109%. Possible metabolite 2-hydroxylated linezolid potentially mediated by cytochrome P450 2 J2 was not detected in the plasma or synovial fluid samples under the current clinical setting after multiple doses.

Conclusions: These results implied nearly equivalent concentrations of linezolid in plasma and synovial fluid of clinical patients with knee osteoarthritis acutely infected with Staphylococcus aureus.
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http://dx.doi.org/10.1186/s40780-022-00248-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248088PMC
July 2022

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Drug Metab Dispos 2022 Jun 30. Epub 2022 Jun 30.

Lab. of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Japan.

Many drug oxygenations are mainly mediated by polymorphic cytochromes P450 (P450s) and also by flavin-containing monooxygenases (FMOs). More than 50 years of research on P450/FMO-mediated drug oxygenations have clarified their catalytic roles. The natural product coumarin causes hepatotoxicity in rats via the reactive coumarin 3,4-epoxide, a reaction catalyzed by P450 1A2; however, coumarin undergoes rapid 7-hydroxylation by polymorphic P450 2A6 in humans. The primary oxidation product of the teratogen thalidomide in rats is deactivated 5'-hydroxythalidomide plus sulfate and glucuronide conjugates; however, similar 5'-hydroxythalidomide and 5-hydroxythalidomide are formed in rabbits Thalidomide causes human P450 3A enzyme induction in liver (and placenta) and is also activated and by P450 3A through the primary human metabolite 5-hydroxythalidomide (leading to conjugation with glutathione/nonspecific proteins). Species differences exist in terms of drug metabolism in rodents and humans, and such differences can be very important when determining the contributions of individual enzymes. The approaches used for investigating the roles of human P450 and FMO enzymes in understanding drug oxidations and clinical therapy have not yet reached maturity and still require further development. Drug oxidations in animals and humans mediated by P450s and FMOs are important for understanding the pharmacological properties of drugs, such as the species-dependent teratogenicity of the reactive metabolites of thalidomide and the metabolism of food-derived odorous trimethylamine to non-odorous (but proatherogenic) trimethylamine -oxide. Recognized differences exist in terms of drug metabolism between rodents, non-human primates, and humans, and such differences are important when determining individual liver enzyme contributions with substrates in and systems.
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http://dx.doi.org/10.1124/dmd.121.000742DOI Listing
June 2022

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Drug Metab Dispos 2022 Jun 30. Epub 2022 Jun 30.

Lab. Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Japan

Dogs are frequently used in drug metabolism studies, and their important drug-metabolizing enzymes, including cytochromes P450 (P450 or CYP), have been analyzed. In humans, CYP3A4 is an especially important P450 due to its abundance and major roles in liver and intestine. In the present study, dog CYP3A98 and CYP3A99 were identified and characterized, along with previously identified CYP3A12 and CYP3A26. The dog CYP3A cDNAs contained open reading frames of 503 amino acids and shared high sequence identity (78-80%) with human CYP3As. Among the dog CYP3A mRNAs, CYP3A98 mRNA was expressed most abundantly in small intestine. In contrast, dog CYP3A12 and CYP3A26 mRNAs were expressed in liver, where CYP3A12 mRNA was the most abundant. The four genes had similar gene structures and formed a gene cluster in the dog and human genomes. Metabolic assays of dog CYP3A proteins heterologously expressed in indicated that the dog CYP3As tested were functional enzymes with respect to typical human CYP3A4 substrates. Dog CYP3A98 efficiently catalyzed oxidations of nifedipine, alprazolam, and midazolam, indicating major roles of CYP3A98 in small intestine. Dog CYP3A12 and CYP3A26 metabolizing nifedipine and/or midazolam would play roles in these reactions in liver. In contrast, dog CYP3A99 showed minimal mRNA expression and minimal metabolic activity, and its contribution to overall drug metabolism is therefore negligible. These results indicated that newly identified dog CYP3A98, a testosterone 6b- and estradiol 16a-hydroxylase, was abundantly expressed in small intestine and is likely the major CYP3A in small intestine in combination with liver-specific CYP3A12. Novel dog cytochromes P450 3A98 (CYP3A98) and CYP3A99 were identified and characterized to be functional and highly identical to human CYP3A4. Known CYP3A12 and new CYP3A98 efficiently catalyzed estradiol 16α-hydroxylation and midazolam 1'-hydroxylation. CYP3A98 mRNA was expressed in small intestine, whereas CYP3A12 mRNA was predominant in liver. Dog CYP3A12 and CYP3A98, in liver and small intestine, respectively, are the enzymes likely responsible for the metabolic clearances of orally administered drugs, unlike human CYP3A4/5, which are in both liver and intestine.
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http://dx.doi.org/10.1124/dmd.121.000749DOI Listing
June 2022

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Drug Metab Dispos 2022 Jun 29. Epub 2022 Jun 29.

Lab. Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Japan

Arylamine -acetyltransferases (NATs) are drug-metabolizing enzymes essential for the metabolism of endogenous substrates and xenobiotics. The molecular characteristics of NATs have been extensively investigated in humans but remain to be investigated in common marmosets and pigs, animal species that are often used in drug metabolism studies. In this study, marmoset NAT1 and pig NAT1 cDNAs were isolated from liver samples and were characterized by molecular analyses and drug-metabolism assays. These genes were intronless and formed gene clusters with one other gene in the genome, just as human genes do. Marmoset NAT1 and pig NAT1 amino acid sequences showed high sequence identities (94% and 85%, respectively) to human NAT1. Phylogenetic analysis indicated that marmoset and pig were more closely clustered with human NATs than with rat or mouse NATs. Marmoset NAT1 and pig NAT1 mRNAs were expressed in all the tissue types analyzed, with the expression levels being highest in small intestine. Metabolic assays using recombinant proteins found that marmoset NAT1 and pig NAT1 metabolized human NAT substrates -aminobenzoic acid, 2-aminofluorene, sulfamethazine, and isoniazid. Marmoset NAT1 and pig NAT1 substantially acetylated -aminobenzoic acid and 2-aminofluorene relevant human NAT1, but their activities were lower toward sulfamethazine and isoniazid than those of the relevant human NAT2. Therefore, marmoset and pig NATs are functional enzymes with molecular similarities to human NAT1, but their substrate specificities, while similar to human NAT1, differ somewhat from human NAT2. Marmoset -acetyltransferase NAT1 and pig NAT1 were identified and showed high sequence identities to human NAT1. These NAT mRNAs were expressed in various tissues. Marmoset and pig NAT1s acetylated typical human NAT substrates, although their substrate specificities differed somewhat from human NAT2. Marmoset NAT1 and pig NAT1 have similarities with human NAT1 in terms of molecular and enzymatic characteristics.
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http://dx.doi.org/10.1124/dmd.122.000919DOI Listing
June 2022

Low cerebrospinal fluid-to-plasma ratios of orally administered lenalidomide mediated by its low cell membrane permeability in patients with hematologic malignancies.

Ann Hematol 2022 Sep 22;101(9):2013-2019. Epub 2022 Jun 22.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan.

Lenalidomide is a synthetic analog of thalidomide formed by the removal of one keto group (plus the addition of an amino group); it has anti-tumor activities beneficial for the treatment of hematologic malignancies. However, lenalidomide distribution to brain in animal models is reportedly low compared with that of thalidomide. The aim of this study was to evaluate plasma and cerebrospinal fluid concentrations of lenalidomide in three patients with malignant hematologic malignancies. Lenalidomide was detected in plasma from the three Japanese patients 1.5 h following oral administration of 20 mg lenalidomide using liquid chromatography/mass spectrometry, despite the in vitro gastrointestinal permeability of lenalidomide being low. Clinically observed cerebrospinal fluid-to-plasma ratios of lenalidomide were low (1.3-2.4%). Observed influx permeability values for lenalidomide in monkey blood-brain barrier model and human placental cell systems were one order of magnitude lower than those of thalidomide and another second-generation drug, pomalidomide along with a positive permeability control, caffeine. Because of the low cell-barrier permeability of lenalidomide demonstrated in in vitro assays, clinically relevant pharmacokinetic profiles of lenalidomide resulted in low penetrability from plasma into cerebrospinal fluid in patients with hematologic malignancies. Lenalidomide is conclusively suggested to expert its favorable immunomodulatory effects via systemic exposures in the patients.
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http://dx.doi.org/10.1007/s00277-022-04893-wDOI Listing
September 2022

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Drug Metab Dispos 2022 Jun 14. Epub 2022 Jun 14.

Lab. Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Japan

Cytochromes P450 (P450 or CYP) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized. The cDNAs of these CYP2Js contained open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and shared high sequence identity (77-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven genes contain nine coding exons and are located in corresponding genomic regions, with the pig genes forming a gene cluster. These CYP2J2 mRNAs were predominantly expressed in small intestine with additional expression in kidney and brain for dog CYP2J2 and pig CYP2J91 mRNAs, respectively. All seven CYP2Js metabolized human CYP2J2 substrates terfenadine, ebastine, and astemizole, indicating that they are functional enzymes. Dog CYP2J2 and pig CYP2J34 and CYP2J35 efficiently catalyzed ebastine primary hydroxylation and secondary carebastine formation at low substrate concentrations, just as human CYP2J2 does. Velocityversus-substate plots exhibited sigmoidal relationships for dog CYP2J2, cat CYP2J2, and pig CYP2J33, indicating allosteric interactions. These results suggest that dog, cat, and pig CYP2Js have similar functional characteristics to human CYP2J2, with slight differences in ebastine and astemizole oxidations. New dog cytochrome P450 2J2 (CYP2J2); cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, homologous to human CYP2J2, were identified and characterized by sequence, phylogenetic, and genomic structure analyses. Intestinal expression patterns of CYP2J mRNAs were characteristic in dogs, cats, and pigs. Dog, cat, and pig CYP2Js likely play roles as drug-metabolizing enzymes in small intestine, similar to human CYP2J2.
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http://dx.doi.org/10.1124/dmd.122.000930DOI Listing
June 2022

Molecular and functional characterization of flavin-containing monooxygenases in pigs, dogs, and cats.

Biochem Pharmacol 2022 08 8;202:115125. Epub 2022 Jun 8.

Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address:

Flavin-containing monooxygenases (FMOs) are drug-oxygenating enzymes that are present in the human genome as FMO1-5 and FMO6P. Among pig, dog, and cat FMOs, pig and dog FMO1 and FMO3 have been partly characterized, but other FMOs have not been systematically identified. In this study, orthologous FMO cDNAs were isolated from pig, dog, and cat livers and evaluated by sequence and phylogenetic analyses, tissue expression, and catalytic function. The amino acid sequences of pig, dog, and cat FMO1-5 shared high sequence identities (83-89%) with human FMO1-5 and were closely clustered in a phylogenetic tree. The gene structure and genomic organization of FMO1-5 were conserved across these species. Dog and pig FMO6P contained insertions of 1 and 83 bases, respectively, and are possibly pseudogenes similar to human FMO6P. Among the tissue types analyzed, pig FMO1 mRNA was abundant in liver, kidney, and lung; dog FMO3, FMO2, and FMO5 mRNAs were abundant in liver, lung, and kidney, respectively; cat FMO1 and FMO3 mRNAs were abundant in kidney and liver, respectively. Recombinant pig and dog FMO1-5 and cat FMO1-6 all mediated benzydamine and trimethylamine N-oxygenations and methyl p-tolyl sulfoxide S-oxygenation. The selective human FMO3 substrate trimethylamine was predominantly metabolized by pig FMO1, dog FMO3, and cat FMO3. Cat FMO6 was also active toward trimethylamine. These results suggest some similarities in the drug-metabolizing capabilities of FMO3 in dogs, cats, and humans and that dog and cat FMO3 generally have molecular and functional characteristics similar to human FMO3, being the major FMO in human liver.
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http://dx.doi.org/10.1016/j.bcp.2022.115125DOI Listing
August 2022

Trivariate Linear Regression and Machine Learning Prediction of Possible Roles of Efflux Transporters in Estimated Intestinal Permeability Values of 301 Disparate Chemicals.

Biol Pharm Bull 2022 Aug 27;45(8):1142-1157. Epub 2022 May 27.

Showa Pharmaceutical University.

A system for predicting apparent bidirectional permeability (P) across Caco-2 cells of diverse chemicals has been reported. The present study aimed to investigate the relationship between in silico-generated P (from apical to basal side, P) for 301 substances with diverse structures and a binary classification of the reported roles of efflux P-glycoprotein or breast cancer resistant protein. The in silico log(P/P) values of 70 substances with reported active efflux and 231 substances with no reported active efflux were significantly different (p < 0.01). The probabilities of active efflux transport estimated by trivariate analysis with log MW, log D, and log D for the 70 active-efflux-positive compounds were higher than those of the other 231 substances (p < 0.01); the area under the corresponding receiver operating characteristic (ROC) curve was 0.81. Further probability values estimated using a machine learning algorithm with 30 chemical descriptors as inputs yielded an area under the ROC curve of 0.79. Using a secondary set of 52 efflux-positive and 48 efflux-negative medicines, the final trivariate-generated probabilities resulted in no significant differences between these binary groups (p = 0.09); however, the final machine learning model demonstrated a good area under the ROC curve of 0.79. Consequently, a combination of the previously established system for generating the permeability coefficients across intestinal monolayers (a continuous variable) and the currently proposed system for predicting the roles of additional active efflux (a binary classification) could prove useful; high accuracy was achieved by applying machine learning using in silico-generated chemical descriptors.
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http://dx.doi.org/10.1248/bpb.b22-00221DOI Listing
August 2022

Experimental evidence of tetrahedral symmetry breaking in SiO glass under pressure.

Nat Commun 2022 Apr 28;13(1):2292. Epub 2022 Apr 28.

RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo, 679-5148, Japan.

Bimodal behavior in the translational order of silicon's second shell in SiO liquid at high temperatures and high pressures has been recognized in theoretical studies, and the fraction of the S state with high tetrahedrality is considered as structural origin of the anomalous properties. However, it has not been well identified in experiment. Here we show experimental evidence of a bimodal behavior in the translational order of silicon's second shell in SiO glass under pressure. SiO glass shows tetrahedral symmetry structure with separation between the first and second shells of silicon at low pressures, which corresponds to the S state structure reported in SiO liquid. On the other hand, at high pressures, the silicon's second shell collapses onto the first shell, and more silicon atoms locate in the first shell. These observations indicate breaking of local tetrahedral symmetry in SiO glass under pressure, as well as SiO liquid.
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http://dx.doi.org/10.1038/s41467-022-30028-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9051114PMC
April 2022

Dorsal Trans-Scaphoid Perilunate Fracture-Dislocation in Association with Dorsal Dislocation of the Thumb Carpometacarpal Joint: A Rare Injury Pattern.

J Hand Surg Asian Pac Vol 2022 Apr 19;27(2):385-388. Epub 2022 Apr 19.

Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, Japan.

We report a dorsal trans-scaphoid perilunate fracture-dislocation associated with dorsal dislocation of the thumb carpometacarpal joint in a 25-year-old man. This is a rare injury and we discuss a possible mechanism for the injury. Level V (Therapeutic).
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http://dx.doi.org/10.1142/S2424835522720146DOI Listing
April 2022

Implant removal following open reduction and internal fixation for distal radius fracture: A study based on the Diagnosis Procedure Combination database in Japan.

J Orthop Sci 2022 Apr 12. Epub 2022 Apr 12.

Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan.

Background: The rate of implant removal and the factors influencing its indication in patients with distal radius fracture (DRF) in Japan are unclear.

Methods: We retrospectively evaluated the incidence rate of implant removal in a large cohort of DRF patients obtained from the Diagnosis Procedure Combination database in Japan between April 2014 and March 2019. Patient- and hospital-related factors possibly affecting removal rate, including age, sex, annual number of open reduction and internal fixation (ORIF) for DRF procedures per hospital, number of hospital beds, advanced or general care hospital, and hospital location were analyzed as well. Hospital location was classified into three types based on population and population density as 1) large city, 2) local city, and 3) sparse area.

Results: Implant removal was performed in 3242 (26.3%) of 12,328 DRF patients receiving ORIF. According to multivariate analysis, the significant factors related to a decreased probability of removal were older patients, male, large annual number of ORIF for DRF procedures per hospital, large number of hospital beds, advanced care hospital, and hospital in large city.

Conclusions: This study clarified the current implant removal rate and trends following ORIF for DRF in Japan. Both patient- and hospital-related factors significantly impacted the decision for implant removal.
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http://dx.doi.org/10.1016/j.jos.2022.03.007DOI Listing
April 2022

Comparison of mouse and human cytochrome P450 mediated-drug metabolising activities in hepatic and extrahepatic microsomes.

Xenobiotica 2022 Mar 26;52(3):229-239. Epub 2022 Apr 26.

Laboratory Animal Research Department, Central Institute for Experimental Animals, Kawasaki, Japan.

Despite the importance of mice as a preclinical species in drug testing, their hepatic and extrahepatic drug-metabolising characteristics are poorly understood. Here, we compared the P450-dependent drug oxidation activity in tissue microsomes and distribution patterns of P450 protein/mRNA between humans and mice.The activities of midazolam 1'-/4-hydroxylation in the liver and intestine and chlorzoxazone 6-hydroxylation in the liver were similar in humans and mice. The activities of coumarin 7-hydroxylation, flurbiprofen 4'-hydroxylation, and -mephenytoin 4'-hydroxylation in the liver were higher in humans than in mice. The activities of 7-ethoxyresorufin -deethylation in the liver, 7-pentoxyresorufin -depentylation in the lung/liver/intestine, bufuralol 1'-hydroxylation in the liver/intestine, propafenone 4'-hydroxylation in liver/intestine, and diazepam -demethylation in the liver/intestine were higher in mice than in humans.CYP1A2/2E1 mRNAs were mainly expressed in the livers of humans and mice. Cyp2b9/2b10 mRNAs were abundant in the mouse lung/liver/intestine, but CYP2B6 was mainly expressed in the human liver. CYP2C/2D/3A mRNAs were expressed in the liver and intestine, with the respective proteins detected in tissue microsomes of both humans and mice.These information on P450-dependent drug-metabolising characteristics in hepatic and extrahepatic tissues is useful to understand the similarities and differences between humans and mice in drug metabolism.
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http://dx.doi.org/10.1080/00498254.2022.2066581DOI Listing
March 2022

Cerebral Venous Thrombosis as an Initial Presentation of Ulcerative Colitis.

Case Rep Gastrointest Med 2022 27;2022:9438757. Epub 2022 Mar 27.

Department of Gastroenterology, Tokyo Bay Urayasu Ichikawa Medical Center, 3-4-32 Toudaijima, Urayasu, 279-0001 Chiba, Japan.

Cerebral venous thrombosis (CVT) is a rare complication of ulcerative colitis (UC) that is potentially fatal once it occurs. This report describes a case of CVT that led to a diagnosis of UC. A 48-year-old woman was diagnosed with CVT due to paresthesia and weakness and was hospitalized for treatment. She developed bloody diarrhea on admission and was further diagnosed with UC based on endoscopic and pathologic findings. Treatment of UC with steroids and sulfasalazine was administered immediately. Her condition improved significantly within several days following treatment. After discharge, the patient experienced no recurrence of either CVT or UC flare-up over the last five years. This report describes CVT as an initial presentation of UC. This is also the first report of a long-term follow-up following successful treatment of CVT with concomitant UC.
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http://dx.doi.org/10.1155/2022/9438757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977341PMC
March 2022

Oxidation of 3'-methoxyflavone, 4'-methoxyflavone, and 3',4'-dimethoxyflavone and their derivatives having 5,7-dihydroxyl moieties by human cytochromes P450 1B1 and 2A13.

Xenobiotica 2022 Feb 13;52(2):134-145. Epub 2022 Apr 13.

Department of Clinical Nutrition, Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Osaka, Japan.

Oxidation of 3'-methoxyflavone, 4'-methoxyflavone, and 3',4'-dimethoxyflavone and their derivatives containing 5,7-dihydroxyl groups by human cytochrome P450 (P450 or CYP) 1B1 and 2A13 was determined using LC-MS/MS systems.3'-Methoxyflavone and 4'-methoxyflavone were mainly -demethylated to form 3'-hydroxyflavone and 4'-hydroxyflavone, respectively, and then 3',4'-dihydroxyflavone at higher rates with CYP1B1 than with CYP2A13. 4'-Methoxy-5,7-dihydroxyflavone (acacetin) was found to be demethylated by CYP1B1 and 2A13 to form 4',5,7-trihydroxyflavone (apigenin) at rates of 0.098 and 0.42 min, respectively. 3'-Methoxy-5,7-dihydroxyflavone was also demethylated by both P450s, with CYP2A13 being more active.3',4'-Dimethoxyflavone was a good substrate for CYP1B1 but not for CYP2A13 and was found to be mainly -demethylated to form 3',4'-dihydroxyflavone (at a rate of 4.2 min) and also several ring-oxygenated products having 299 fragments. Molecular docking analysis supported the proper orientation for formation of these products by CYP1B1.Our present results showed that 3'- and 4'-methoxyflavone can be oxidised to their -demethylated products and, to a lesser extent, to ring oxidation products by both P450s 1B1 and 2A13 and that 3',4'-dimethoxyflavone is a good substrate for CYP1B1 in forming both -demethylated and ring-oxidation products. Introduction of a 57diOHF moiety into these methoxylated flavonoids caused decreased in oxidation by CYP1B1 and 2A13.
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http://dx.doi.org/10.1080/00498254.2022.2062486DOI Listing
February 2022

Probe drug T-1032 N-oxygenation mediated by cytochrome P450 3A5 in human hepatocytes in vitro and in humanized-liver mice in vivo.

Drug Metab Pharmacokinet 2022 Jun 18;44:100453. Epub 2022 Feb 18.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan. Electronic address:

Polymorphic cytochrome P450 3A5 (CYP3A5) expression contributes to individual differences in the pharmacokinetics of probe drugs. The identification of suitable in vivo CYP3A5 probes would benefit drug metabolism and drug interaction studies using chimeric mice with humanized liver. In this study, we investigated the pharmacokinetic profiles of T-1032, which is known as an in vitro CYP3A5 probe substrate, using humanized-liver mice. Substantial N-oxygenation of T-1032 was observed in hepatocytes from humans and from humanized-liver mice. Hepatocytes from the human donor genotyped as CYP3A5∗3/∗3 (poor expressers) showed significantly lower T-1032 N-oxidation rates than those from donors harboring CYP3A5∗1. After a single oral dose of T-1032 (1.0 mg/kg) in humanized-liver mice, the plasma levels of T-1032 N-oxide were higher in five mice with CYP3A5∗1/∗7 hepatocytes than in four mice with CYP3A5∗3/∗3 hepatocytes. The maximum concentrations of T-1032 N-oxide after oral administration of T-1032 in humanized-liver mice with CYP3A5∗1/∗7 hepatocytes were twice (a significant difference) those from humanized-liver mice with CYP3A5∗3/∗3 hepatocytes. These results suggest that polymorphic CYP3A5-dependent T-1032 N-oxidation was observed in humanized liver mice in vitro and in vivo. However, the contribution of CYP3A5 genotypes may have little or only limited effects on the overall pharmacokinetic profiles of T-1032 in vivo.
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http://dx.doi.org/10.1016/j.dmpk.2022.100453DOI Listing
June 2022

Cytochrome P450-dependent drug oxidation activities and their expression levels in liver microsomes of chimeric TK-NOG mice with humanized livers.

Drug Metab Pharmacokinet 2022 Jun 25;44:100454. Epub 2022 Feb 25.

Central Institute for Experimental Animals, Kawasaki, Japan.

Hepatic cytochrome P450 (P450)-dependent drug oxidation activity has not been completely characterized in chimeric TK-NOG mice with humanized livers (humanized liver mice). In this study, we examined several drug oxidation activities catalyzed by liver microsomes from humans, humanized liver mice, and TK-NOG mice using 9 P450 substrates. The catalytic activities of liver microsomes from humans and humanized liver mice showed relatively similar rates of oxidation of 7-ethoxyresorufin, coumarin, 7-pentoxyresorufin, flurbiprofen, S-mephenytoin, chlorzoxazone, and midazolam, whereas bufuralol 1'-hydroxylation and propafenone 4'-hydroxylation (rodent-specific propafenone oxidation activity) were higher in humanized liver mice than in humans. In addition, P450 protein expression levels in the humanized mouse liver were quantified using a liquid chromatography-tandem mass spectrometry-based protein quantification method. Quantification of P450 enzymes showed a 3-fold difference between human and humanized liver mouse livers, except for CYP2B6, which showed an approximately 6-fold difference. Overall, most P450-dependent drug oxidation activities were comparable between liver microsomes from human and humanized liver mice based on the similar expression levels of human P450 enzymes. However, some differences were observed between both species, including considerable differences in bufuralol 1'-hydroxylation and propafenone 4'-hydroxylation activities.
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http://dx.doi.org/10.1016/j.dmpk.2022.100454DOI Listing
June 2022

Long-Term Limitation Effects of Se(VI), Zn(II), and Ni(II) on Start-Up of the Anammox Process Using Gel Carrier.

Front Bioeng Biotechnol 2022 4;10:851617. Epub 2022 Mar 4.

Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.

Anaerobic ammonia oxidation (anammox) bacteria are inhibited by heavy metals at high concentrations but require trace amounts of some heavy-metal elements for growth and activity maintenance. The present study evaluates the long-term limitation effects of Se(VI), Zn(II), and Ni(II) on the start-up period of an anammox reactor. To strictly limit the levels of heavy metals in the reactor, all tests used ultrapure water as the influent synthetic wastewater and all reactors were installed in a clean booth. The anammox biomass was maintained through the gel entrapment technique. In the absence of Se(VI) and Ni(II), the anammox reactor start-up was 18.9 kg-N (m-carrier d) (nitrogen conversion rate (NCR) per gel carriers), indicating that Se(VI) and Ni(II) are not required or need not be continuously added to maintain the anammox process. Under Zn(II) limitation, the anammox process failed to start-up and the NCR tended to decrease rapidly. After readdition of 0.005 mg L of Zn(II), the NCR did not decline further and instead partially recovered at a very slow rate. The NCR was completely recovered after adding 0.020 mg L of Zn(II). These results reveal that Zn(II) limitation seriously affects the start-up of the anammox process while Se(VI) and Ni(II) are not required or need not be continuously added to the anammox process.
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http://dx.doi.org/10.3389/fbioe.2022.851617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931481PMC
March 2022

High Riding Jugular Bulb Protruding Into Tympanic Cavity: Longitudinal Radiologic Study in a Deaf Child.

Ear Nose Throat J 2022 Feb 23:1455613221079494. Epub 2022 Feb 23.

Comprehensive Ear and Hearing Center, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan.

Background: High riding jugular bulb (HRJB) develops after 2 years and is rare at younger ages. High riding jugular bulb sometimes protrudes into the tympanic cavity, which can cause hemorrhagic complications during otologic surgery.

Case Presentation: We describe a congenitally deaf child with bilateral inner ear malformations and a right-sided HRJB on CT at 9 months. This child had undergone left cochlear implantation (CI) at 19 months, and right CI was planned at 6 years. However, we decided not to perform the right CI because preoperative CT images revealed that the right jugular bulb (JB) was enlarged and protruded into the tympanic cavity, completely covering the round window (RW).

Conclusion: This is the first pediatric case in which a longitudinal CT scan proves that HRJB develops and protrudes over time. These findings suggest that the earlier the HRJB forms, the larger it may grow. We must keep in mind the possibility of the enlargement and protrusion of HRJB.
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http://dx.doi.org/10.1177/01455613221079494DOI Listing
February 2022

Imaging Mass Spectrometry (IMS) for drug discovery and development survey: Results on methods, applications and regulatory compliance.

Drug Metab Pharmacokinet 2022 Apr 16;43:100438. Epub 2021 Dec 16.

Leader of Japan Association for Imaging Mass Spectrometry, Drug Metabolism and Pharmacokinetics, Laboratory for Drug Discovery and Development, Shionogi & Co., Ltd., 3-1-1, Futaba, Toyonaka, Osaka, 561-0825, Japan. Electronic address:

Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.
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http://dx.doi.org/10.1016/j.dmpk.2021.100438DOI Listing
April 2022

Systematic identification and characterization of cynomolgus macaque solute carrier transporters.

Drug Metab Pharmacokinet 2022 Apr 4;43:100437. Epub 2021 Dec 4.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan. Electronic address:

Cynomolgus macaques are used in preclinical studies in part because of their evolutionary closeness to humans. However, drug transporters [including solute carrier (SLC) transporters] essential for the absorption and excretion of drugs have not been fully investigated at the molecular level in cynomolgus macaques. We identified and characterized cynomolgus macaque SLC15A1, SLC15A2, SLC22A1, SLC22A2, SLC22A6, SLC22A8, SLC47A1, and SLC47A2, along with SLCO (formerly SLC21A) transporters SLCO1A2, SLCO1B1, SLCO1B3, and SLCO2B1. These cynomolgus SLC transporters had high amino acid sequence identities (92-97%) with their human orthologs and contained sequence motifs characteristic of SLC transporters. Phylogenetic analysis showed that these cynomolgus SLC transporters were more closely clustered with their human orthologs than with those of dogs, rats, or mice. Gene structure and genomic organization were similar in macaques and humans. Cynomolgus SLC transporter mRNAs showed distinct tissue expression patterns, being most abundantly expressed in jejunum (SLC15A1), liver (SLC22A1, SLCO1B1, and SLCO2B1), and kidney (SLC15A2, SLC22A2, SLC22A6, SLC22A8, SLC47A1, SLC47A2, and SLCO1A2). In contrast, cynomolgus SLCO2B1 mRNA was more ubiquitously expressed. Among these SLC mRNAs, the most abundant in liver was SLCO1B1, in jejunum SLC15A1, and in kidney SLC22A2. These results suggest similar characteristics of SLC transporters in cynomolgus macaques and humans.
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http://dx.doi.org/10.1016/j.dmpk.2021.100437DOI Listing
April 2022

Cloning and tissue expression of ATP-binding cassette transporters in cynomolgus macaques.

Drug Metab Pharmacokinet 2022 Feb 2;42:100431. Epub 2021 Nov 2.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan. Electronic address:

Cynomolgus macaques are used in preclinical studies in part because of their evolutionary closeness to humans. However, drug transporters, including ATP-binding cassette (ABC) transporters, which are essential for the absorption and excretion of drugs, have not been fully investigated at the molecular level in cynomolgus macaques. In this study, ABCB4, ABCC3, ABCC4, and ABCG2 cDNAs were newly identified and characterized, along with ABCB1, ABCB11, and ABCC2 cDNAs previously identified, in cynomolgus macaques. All seven cynomolgus ABC transporters had high sequence identities (96-98%) with their human orthologs in terms of amino acid sequences and were also most closely clustered with their human orthologs by phylogenetic analysis. Furthermore, the gene structures and genomic organization were similar in cynomolgus macaques and humans. The mRNAs of these cynomolgus ABC transporters, as analyzed using the quantitative polymerase chain reaction, showed distinct tissue expression patterns. Among the ten tissues, ABCB1, ABCC2, ABCC3, and ABCG2 mRNAs were most abundantly expressed in jejunum; ABCB4 and ABCB11 in liver; and ABCC4 in kidney, which are similar to the expression patterns of human ABC transporters. These results suggest molecular similarities of the ABC transporters in cynomolgus macaques and humans.
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http://dx.doi.org/10.1016/j.dmpk.2021.100431DOI Listing
February 2022

Drug-oxidizing and conjugating non-cytochrome P450 (non-P450) enzymes in cynomolgus monkeys and common marmosets as preclinical models for humans.

Biochem Pharmacol 2022 03 27;197:114887. Epub 2021 Dec 27.

Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address:

Many drug oxidations and conjugations are mediated by a variety of cytochromes P450 (P450) and non-P450 enzymes in humans and non-human primates. These non-P450 enzymes include aldehyde oxidases (AOX), carboxylesterases (CES), flavin-containing monooxygenases (FMO), glutathione S-transferases (GST), arylamine N-acetyltransferases (NAT),sulfotransferases (SULT), and uridine 5'-diphospho-glucuronosyltransferases (UGT) and their substrates include both endobiotics and xenobiotics. Cynomolgus macaques (Macaca fascicularis, an Old-World monkey) are widely used in preclinical studies because of their genetic and physiological similarities to humans. However, many reports have indicated the usefulness of common marmosets (Callithrix jacchus, a New World monkey) as an alternative non-human primate model. Although knowledge of the drug-metabolizing properties of non-P450 enzymes in non-human primates is relatively limited, new research has started to provide an insight into the molecular characteristics of these enzymes in cynomolgus macaques and common marmosets. This mini-review provides collective information on the isoforms of non-P450 enzymes AOX, CES, FMO, GST, NAT, SULT, and UGT and their enzymatic profiles in cynomolgus macaques and common marmosets. In general, these non-P450 cynomolgus macaque and marmoset enzymes have high sequence identities and similar substrate recognitions to their human counterparts. However, these enzymes also exhibit some limited differences in function between species, just as P450 enzymes do, possibly due to small structural differences in amino acid residues. The findings summarized here provide a foundation for understanding the molecular mechanisms of polymorphic non-P450 enzymes and should contribute to the successful application of non-human primates as model animals for humans.
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http://dx.doi.org/10.1016/j.bcp.2021.114887DOI Listing
March 2022

Plasma Concentration Profiles for Hepatotoxic Pyrrolizidine Alkaloid Senkirkine in Humans Extrapolated from Rat Data Sets Using a Simplified Physiologically Based Pharmacokinetic Model.

Drug Metab Bioanal Lett 2022 ;15(1):64-69

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.

Aim: The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available.

Background: The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed.

Objective: The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans.

Methods: Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model.

Results: After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells.

Conclusion: Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.
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http://dx.doi.org/10.2174/1872312801666211220110055DOI Listing
January 2022
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