Publications by authors named "Lilian Y Li"

17 Publications

  • Page 1 of 1

Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.

J Med Chem 2020 11 15;63(21):12725-12747. Epub 2020 Oct 15.

Southern Research Institute, 2000 9th Avenue South, Birmingham, Alabama 35205 United States.

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL) in a post-translational processing step that is critical for coronavirus replication. The 3CL sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL employing ligand-protease structures solved by X-ray crystallography led to the identification of and . Preclinical experiments reveal () as a potent inhibitor of CoV-2 3CL with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571312PMC
November 2020

Schizotypy dimensions are associated with altered resting state alpha connectivity.

Int J Psychophysiol 2020 09 26;155:175-183. Epub 2020 Jun 26.

Department of Psychological Science, University of California, Irvine, Irvine, CA, USA. Electronic address:

The disconnection hypothesis of schizophrenia says that symptoms are explained by dysfunctional connections across a wide range of brain networks. Despite some support for this hypothesis, there have been mixed findings. One reason for these may be the multidimensional nature of schizophrenia symptoms. In order to clarify the relationship between symptoms and brain networks, the current study included individuals at risk for schizophrenia-spectrum disorders who either report extreme levels of positive schizotypy traits (perceptual aberrations and magical ideation, or "PerMag"; n = 23), or an extreme negative schizotypy trait (social anhedonia, or "SocAnh"; n = 19), as well as a control group (n = 18). Resting-state alpha electroencephalography was collected, and functional networks for each subject were measured using the phase-lag index to calculate the connectivity between channel pairs based on the symmetry of instantaneous phase differences over time. Furthermore, graph theory measures were introduced to identify network features exclusive to schizotypy groups. We found that the PerMag group exhibited a smaller difference in node strength and clustering coefficient in frontal/occipital and central/occipital regional comparisons compared to controls, suggesting a more widespread network. The SocAnh group exhibited a larger difference in degree in the central/occipital regional comparison relative to controls, suggesting a localized occipital focus in the connectivity network. Regional differences in functional connectivity suggest that different schizotypy dimensions are manifested at the network level by different forms of disconnections. Taken together, these findings lend further support to the disconnection hypothesis and suggest that altered connectivity networks may serve as a potential biomarker for schizophrenia risk.
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http://dx.doi.org/10.1016/j.ijpsycho.2020.06.012DOI Listing
September 2020

Differential item functioning of the Multidimensional Schizotypy Scale and Multidimensional Scale-Brief across ethnicity.

Psychol Assess 2020 Apr 16;32(4):383-393. Epub 2020 Jan 16.

Department of Psychology.

Schizotypy refers to traits or symptoms similar to schizophrenia, but in a diminished form, and schizotypy is thought to reflect a liability for the future development of schizophrenia. The Multidimensional Schizotypy Scale (MSS) is a new measure of schizotypy that improves on existing measures. The MSS contains full and brief subscales for positive, negative, and disorganized schizotypy. Although MSS scores have been validated in a variety of populations, the scales have not been thoroughly examined for differential item functioning in East Asian, Southeast Asian, Hispanic, Multiracial, and White participants. The current study included 567 East Asian, 351 Southeast Asian, 360 Hispanic, 230 Multiracial, and 345 White undergraduate participants from the United States. Overall, few of the items in the full or brief versions of the scales displayed differential item functioning across groups. The full and brief versions of the scales also displayed similar and not-significantly different validity coefficients with the Detachment and Psychoticism scales of the Personality Inventory for . These findings suggest that the MSS measures the same constructs across ethnic groups, and the scale scores represent the same latent level of schizotypy among groups. Future research may use the MSS in these diverse groups without concern that the psychometric properties differ significantly among groups. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000798DOI Listing
April 2020

Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies.

J Clin Pharmacol 2020 04 19;60(4):515-527. Epub 2019 Nov 19.

Global Clinical Pharmacology, Janssen Research & Development, Beerse, Belgium.

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half-life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α -acid-glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up-titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted.
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http://dx.doi.org/10.1002/jcph.1547DOI Listing
April 2020

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

Eur J Drug Metab Pharmacokinet 2020 Feb;45(1):101-111

Janssen Research & Development, Springhouse, PA, USA.

Background And Objectives: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated.

Methods: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (C), area under the curve (AUC) from time 0 to 168 h (AUC), AUC from time 0 to the last quantifiable concentration (AUC), and AUC from time 0 to infinity (AUC) were calculated from individual plasma concentration-time data using standard non-compartmental methods.

Results: Coadministration of erdafitinib with fluconazole increased C of erdafitinib by approximately 21%, AUC by 38%, AUC by 49%, and AUC by 48% while coadministration with itraconazole resulted in no change in erdafitinib C and increased AUC by 20%, AUC by 33% and AUC by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults.

Conclusion: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential.

Trial Registration: ClinicalTrials.gov identifier number: NCT03135106.
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http://dx.doi.org/10.1007/s13318-019-00581-9DOI Listing
February 2020

Effect of Plasma Protein Binding on the Pharmacokinetics of Erdafitinib: Results of an Integrated Cross-Study Analysis.

J Clin Pharmacol 2020 03 10;60(3):391-399. Epub 2019 Oct 10.

Clinical Pharmacology & Pharmacometrics, Quantitative Sciences, Janssen Research & Development, Spring House, Pennsylvania, USA.

Erdafitinib, a potent oral fibroblast growth factor receptor inhibitor, is a low extraction ratio drug highly bound to alpha-1-acid glycoprotein (AGP) with free fraction (f ) varying across populations. This analysis aimed to characterize the impact of plasma protein binding on erdafitinib pharmacokinetics (PK). Plasma protein-binding data (f , AGP, albumin) and PK parameters were pooled from 6 phase 1 studies in healthy participants and 1 first-in-human study in patients with cancer. Binding kinetics were characterized using a nonlinear mixed-effects model. Mean (coefficient of variation, CV%) f was 0.510% (39.4%) for healthy participants and 0.316% (64.0%) for patients, with a 2.1-fold higher AGP and 10% lower albumin. Linear binding of erdafitinib to AGP and albumin was observed, with >1000-fold higher binding constant for AGP than albumin (17.6 vs 0.017 µM ). The f decreased with increasing AGP in a nonlinear relationship. Despite its abundance in plasma relative to AGP, albumin contributed to <4% of the overall binding of erdafitinib (1.8% in patients; 4.0% in healthy participants). The AGP-binding constant was 68.0% lower in predose (spiked) versus postdose (ex vivo) samples. Total oral clearance was generally proportional to the f and higher in healthy participants than in patients, consistent with the differences in AGP. Correcting for f accounted for the majority of the relationship between oral clearance and f as expected with a low extraction ratio drug. Characterizing free erdafitinib concentrations is critical to accounting for differences in f and to further investigating its clinical relevance.
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http://dx.doi.org/10.1002/jcph.1529DOI Listing
March 2020

Assessment of the effect of erdafitinib on cardiac safety: analysis of ECGs and exposure-QTc in patients with advanced or refractory solid tumors.

Cancer Chemother Pharmacol 2019 09 6;84(3):621-633. Epub 2019 Jul 6.

Janssen Research and Development, Spring House, PA, USA.

Purpose: To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors.

Methods: Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2-4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration-QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data.

Results: Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration-QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as - 0.00269 ms/(ng/mL) and - 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was < 10 ms at the upper bound of the two-sided 90% confidence interval.

Conclusions: ECG data and the concentration-QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters. Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34.
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http://dx.doi.org/10.1007/s00280-019-03896-1DOI Listing
September 2019

Emotional response in schizophrenia to the "36 questions that lead to love": Predicted and experienced emotions regarding a live social interaction.

PLoS One 2019 27;14(2):e0212069. Epub 2019 Feb 27.

Department of Psychological Science, University of California, Irvine, Irvine, CA, United States of America.

Evidence suggests that individuals with schizophrenia (SZ) report anticipatory pleasure deficits compared to controls and that these deficits are linked to decreased motivation to engage socially. However, these deficits have been identified via self-report measures of hypothetical pleasant stimuli, leaving it unclear whether they exist in reference to actual social situations. To address this issue, we created a live social interaction that minimized the reliance of higher-order cognitive processes. SZ and control participants were told that they would be playing an "enjoyable sharing game" with another study participant (who was actually a confederate) that involved asking and answering questions (36 interpersonal closeness generation questions; Aron et al., 1997). Participants then reported their current mood and the emotions they anticipated experiencing during the pleasant social interaction. Immediately following the interaction, they reported their experienced emotions. We found that the SZ group anticipated more negative emotion (d = 1.0), but were less accurate in forecasting negative emotion (d = .81), than controls, and these effects were large. There were small, non-significant group differences in anticipation, experience, and accuracy in forecasting of positive emotion (all ds < .29). Also, social anhedonia was positively correlated with anticipated negative affect and negatively associated with experienced positive emotion. At the same time, controls reported finding the interaction to be a more positive emotional experience overall, d = 0.75. This is the first study to show that "anticipatory pleasure deficits" in SZ might actually be heightened anticipated negative emotion and that inaccurate forecasting could be linked to decreased social motivation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392255PMC
November 2019

Novel benzamide-based histamine h3 receptor antagonists: the identification of two candidates for clinical development.

ACS Med Chem Lett 2015 Apr 13;6(4):450-4. Epub 2015 Mar 13.

Janssen Pharmaceutical Company, a division of Johnson & Johnson Pharmaceutical Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.

The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
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http://dx.doi.org/10.1021/ml5005156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394347PMC
April 2015

Haemodynamic effects, safety, and pharmacokinetics of human stresscopin in heart failure with reduced ejection fraction.

Eur J Heart Fail 2013 Jun 6;15(6):679-89. Epub 2013 Mar 6.

Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Ave., Suite 1006, Chicago, IL 60611, USA.

Aims: Human stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤ 35% and cardiac index (CI) ≤ 2.5 L/min/m(2).

Methods And Results: Sixty-two patients with HF and LVEF ≤ 35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ-39588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ-39588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen.

Conclusion: In HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP.

Trial Registration: NCT01120210.
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http://dx.doi.org/10.1093/eurjhf/hft023DOI Listing
June 2013

Synthesis and SAR of 4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors.

Bioorg Med Chem Lett 2009 Apr 13;19(8):2099-102. Epub 2009 Mar 13.

Pfizer Global R&D, San Diego, CA 92121, USA.

The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.
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http://dx.doi.org/10.1016/j.bmcl.2009.03.023DOI Listing
April 2009

Factors influencing regional differences in intestinal absorption of UK-343,664 in rat: possible role in dose-dependent pharmacokinetics.

J Pharm Sci 2006 Feb;95(2):435-45

School of Pharmacy, University of Washington, Seattle, 98195-7610, USA.

The objective of this study was to evaluate potential contributions of intestinal export and metabolism to the oral dose-dependent pharmacokinetics of the human cGMP-specific phosphodiesterase type 5 inhibitor, UK-343,664. Differences between jejunal and ileal handling of this CYP3A and P-gp substrate were investigated. CYP3A and P-gp display differing activities in the upper and lower mammalian small intestine and their impact on variable drug absorption can be mechanistically assessed for individual compounds with in situ perfusion of rat's small intestine. Isolated segments of rat jejunum and ileum were perfused with UK-343,664 solution and measurements were made as a function of drug concentration for dose dependence and in the presence of CYP3A and P-gp inhibitors. Intestinal permeability and metabolism were measured by total drug disappearance and major metabolite, UK-347,334 (N-desethyl metabolite), appearance in the intestinal lumen. Intestinal tissue and mesenteric blood measurements of drug and metabolite were also determined. The effective permeability (P(eff)) of UK-343,664 and metabolite formation (F(met)) increased as a function of concentration. Regional differences in P(eff) and F(met) were observed with low-intestinal metabolism of UK-343,664 in both regions (<10%). P-gp inhibition caused significant increase in P(eff) and F(met) in jejunum and ileum while ketoconazole, a P-gp and CYP3A inhibitor, has only limited effect on metabolism. In conclusion, UK-343,664 absorption is mainly regulated by P-gp in jejunum and ileum while CYP3A intestinal metabolism has minimal effect. This role of P-gp could explain the dose-dependent pharmacokinetics of UK-343,664 and its unusual behavior of t(max) as a function of dose.
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http://dx.doi.org/10.1002/jps.20527DOI Listing
February 2006

The effects of thermal injury on transcellular permeability and intestinal P-glycoprotein in rats.

Burns 2003 Dec;29(8):803-9

The University of Wisconsin School of Pharmacy, Madison, WI, USA.

This study was designed to assess intestinal drug transport via transcellular absorption and intestinal P-glycoprotein content following thermal injury in rats using propranolol as a marker substrate. Male, Sprague Dawley rats (n=30) underwent either a 30% total body surface area full thickness burn or sham treatment. Twenty-four hours later, animals were anesthetized, underwent laparotomy and the proximal jejunum was cannulated. The jejunal segment was perfused with buffer containing [3H] propranolol. Following euthanasia, jejunal tissue was harvested for Western immunoblotting of P-glycoprotein and villin, and immunohistochemical analysis of P-glycoprotein. Dramatic structural changes in jejunal integrity were observed following thermal injury; however, no significant differences in the absorption characteristics of propranolol following thermal injury were observed. Mean effective permeability of propranolol was 5.67+/-1.79 and 5.85+/-1.67cm/sx10(-5) for burn and sham groups, respectively (P>0.05). P-glycoprotein and villin content in the jejunum were significantly decreased in burn animals. The transcellular transport of propranolol is unaffected 24h following thermal injury in rats, despite alterations in intestinal P-glycoprotein content. The decrease in P-glycoprotein and villin content in thermally injured animals may reflect loss of mature enterocytes at the villus tips.
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http://dx.doi.org/10.1016/s0305-4179(03)00195-5DOI Listing
December 2003

Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs.

Int J Pharm 2003 Aug;261(1-2):81-92

College of Pharmacy, The University of Michigan, 428 Church Street, 48109-1065, Ann Arbor, MI, USA.

Many oral phosphate prodrugs have failed to improve the rate or extent of absorption compared to their insoluble parent drugs. Rapid parent drug generation via intestinal alkaline phosphatase can result in supersaturated solutions, leading to parent drug precipitation. The purpose was to (1) investigate whether parent drugs can precipitate from prodrug solutions in presence of alkaline phosphatase; (2) determine whether induction times are influenced by (a) dephosphorylation rate, (b) parent drug supersaturation level, and (c) parent drug solubility. Induction times were determined from increases in optical densities after enzyme addition to prodrug solutions of TAT-59, fosphenytoin and estramustine phosphate. Apparent supersaturation ratios (sigma) were calculated from parent drug solubility at intestinal pH. Precipitation could be generated for all three prodrugs. Induction times decreased with increased enzyme activity and supersaturation level and were within gastrointestinal residence times for TAT-59 concentration>/=21microM (sigma>/=210). Induction times for fosphenytoin were less than the GI residence time (199min) for concentrations of approximately 352 microM (sigma=4.0). At approximately 475 microM (sigma=5.3) the induction times were less than 90min. For estramustine-phosphate, no precipitation was observed within GI residence times. Enzyme-mediated precipitation will depend on apparent supersaturation ratios, parent drug dose, solubility and solubilization by the prodrug.
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http://dx.doi.org/10.1016/s0378-5173(03)00287-4DOI Listing
August 2003

In-vitro crystallization of indinavir in the presence of ritonavir and as a function of pH.

J Pharm Pharmacol 2003 May;55(5):707-11

Division of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.

The aim of this study was to investigate the in-vitro crystallization of indinavir as a function of pH alteration and in the presence of another protease inhibitor, ritonavir. Crystallization processes were studied for indinavir sulfate, indinavir free base and a commercial indinavir capsule dosage form, respectively. Crystallization induction times were determined with varying initial concentration of supersaturated solution, and in the presence or absence of seed material. In-vitro induction times were found to be significantly shorter for the indinavir capsule dosage form compared with that of indinavir sulfate and indinavir free base. Induction times were inversely proportional to the final concentration in pH 7 buffer for all materials, and were significantly shortened in the presence of seeds. The crystal morphology of indinavir varied under different crystallization conditions. This study demonstrated the potential for precipitation of indinavir upon pH elevation, while also suggesting that the presence of impurities or seeding material significantly shortens the induction time for indinavir crystal formation. This induction time period falls well within the gastric emptying time following the intake of a high-caloric meal, and within small intestinal transit time. The results of this study are in agreement with the clinical observation that a high-calorie protein meal significantly reduces the oral bioavailability of indinavir in man, accompanying a pH elevation in the stomach.
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http://dx.doi.org/10.1211/002235703765344630DOI Listing
May 2003

Absorption rate limit considerations for oral phosphate prodrugs.

Pharm Res 2003 Jun;20(6):848-56

The University of Michigan, College of Pharmacy, 428 Church Street, Ann Arbor, Michigan 48109, USA.

Purpose: To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs.

Methods: Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aqueous solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Additional absorption studies were carried out in rats.

Results: Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 microM fosphenytoin, respectively. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 microM. Permeability of the highly lipophilic and protein bound compound, DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was observed for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone solution, but the prodrug solution did yield higher entacapone plasma levels in rats when compared with an entacapone suspension.

Conclusion: Ideal phosphate prodrug candidates are characterized by high permeability and low solubility (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.
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http://dx.doi.org/10.1023/a:1023827017224DOI Listing
June 2003

Intestinal metabolism promotes regional differences in apical uptake of indinavir: coupled effect of P-glycoprotein and cytochrome P450 3A on indinavir membrane permeability in rat.

J Pharmacol Exp Ther 2002 May;301(2):586-93

Division of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.

The purpose of this study was to investigate transport and metabolism contributions to low indinavir permeability in rat ileum and enhanced drug permeability in the jejunum. Permeability models utilized included single pass in situ rat intestinal perfusion and rat intestinal tissue mounted in Ussing chambers. Intestinal metabolism was measured by fractional appearance of metabolite (F(met)), determined as the percentage of the predominant metabolite M6 over luminal loss of indinavir in the perfusion model. Among the results, indinavir exhibited bidirectional transport across rat ileum. Verapamil and cyclosporin A inhibited net flux by 37 and 38%, respectively. Intestinal metabolism of indinavir was most significant in upper jejunum (F(met) = 65.78 +/- 19.02%), decreasing in midjejunum (F(met) = 31.58 +/- 5.63%). M6 was not detectable in ileum or colon. Western blot analysis of rat intestinal mucosal tissue samples confirmed that the axial expression of CYP3A was consistent with the regional pattern of formation of M6. Intestinal metabolism was saturable and could be inhibited by the CYP3A inhibitor, ketoconazole. A low luminal concentration of indinavir (1 microM) was associated with high F(met) (87.90 +/- 14.30%), whereas a high luminal concentration of indinavir (50 microM) was associated with low F(met) (35.84 +/- 11.59%). In the presence of ketoconazole, both F(met) and permeability of indinavir were reduced in the jejunum. These results suggest that 1) intracellular metabolism of indinavir enhances apical uptake of indinavir in the rat jejunum as a function of the increased concentration gradient generated across the epithelial cell membrane and 2) the efflux transporter P-glycoprotein limits apical uptake of indinavir in the ileum, resulting in low apparent permeability.
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http://dx.doi.org/10.1124/jpet.301.2.586DOI Listing
May 2002