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Physiologically Based Pharmacokinetics Model Predicts the Lack of Inhibition by Repaglinide on the Metabolism of Pioglitazone
ConclusionRepaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo,which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro. This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - August 21, 2015 Category: Drugs & Pharmacology Authors: Qingqing Xiao, Liling Tang, Ruijuan Xu, Wei Qian, Jin Yang Tags: Original Paper Source Type: research

Identification and disposition of novel mono‐hydroxyl mefenamic acid and their potentially toxic 1‐O‐acyl‐glucuronides in vivo
Abstract Mefenamic acid (MEF) is a widely prescribed non‐steroidal anti‐inflammatory drug that has been found associated with rare but severe cases of hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. The formation of protein‐reactive acylating metabolites such as 1‐O‐acyl‐MEF glucuronide (MEFG) and 3′‐hydroxymethyl‐MEF 1‐O‐acyl‐glucuronide is one proposed cause. In addition to the well‐reported 3′‐hydroxymethyl‐MEF, two mono‐hydroxyl‐MEF (OH‐MEFs) were recently identified in vitro. However, in vivo evidence is lacking and whether these OH‐MEFs would be further glucuronid...
Source: Biopharmaceutics and Drug Disposition - August 11, 2015 Category: Drugs & Pharmacology Authors: Sophia Yui Kau Fong, Yufeng Zhang, Yin Cheong Wong, Limin Zhou, Quanbin Han, Zhong Zuo Tags: Original Paper Source Type: research

Physiologically based pharmacokinetic modeling to predict complex drug–drug interactions: a case study of AZD2327 and its metabolite, competitive and time‐dependent CYP3A inhibitors
In conclusion, this model simulated DDI with less than a two‐fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways and inhibitors (parent and metabolite) can be predicted using a well‐developed PBPK model. Copyright © 2015 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - July 27, 2015 Category: Drugs & Pharmacology Authors: Jian Guo, Diansong Zhou, Yan Li, Bui H. Khanh Tags: Original Paper Source Type: research

Species‐ and gender‐dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes
In conclusion, glucuronidation of flavonoid aglycones is faster than that of glucosides in the intestine and the liver. Understanding the metabolism and species‐ and gender‐dependent differences between glucosides and aglycones is crucial for development of drugs from flavonoids. This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - July 1, 2015 Category: Drugs & Pharmacology Authors: Peimin Dai, Feifei Luo, Ying Wang, Huangyu Jiang, Liping Wang, Guiyu Zhang, Lijun Zhu, Ming Hu, Xinchun Wang, Linlin Lu, Zhongqiu Liu Tags: Original Paper Source Type: research

Kidney function changes with aging in adults: comparison between cross‐sectional and longitudinal data analyses in renal function assessment
In conclusion, our findings indicated that one should be cautious in interpreting the renal function decline rate with aging information because its estimation was highly depended on the statistical analyses. From our analyses, a population LT analysis (e.g., random coefficient model) is recommended if individualization is critical, such as a dose adjustment based on the renal function during a chronic therapy. This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - July 1, 2015 Category: Drugs & Pharmacology Authors: Sang M. Chung, David J. Lee, Austin Hand, Philip Young, Jayabharathi Vaidyanathan, Chandrahas Sahajwalla Tags: Original Paper Source Type: research

Development of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model to Identify Mechanisms Contributing to Entacapone Low Bioavailability
This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - July 1, 2015 Category: Drugs & Pharmacology Authors: Saeed Alqahtani, Amal Kaddoumi Tags: Original Paper Source Type: research

Therapeutic drug monitoring of cyclosporine and area under the curve prediction using a single time point strategy: appraisal using peak concentration data
This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - July 1, 2015 Category: Drugs & Pharmacology Authors: Nuggehally R. Srinivas Tags: Original Paper Source Type: research

Point mutation of Cytochrome P450 2A6 (a polymorphic allele CYP2A6.25) confers new substrate specificity towards flavonoids
This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - July 1, 2015 Category: Drugs & Pharmacology Authors: Tomohide Uno, Chika Ogura, Chiho Izumi, Masahiko Nakamura, Takeshi Yanase, Hiroshi Yamazaki, Hitoshi Ashida, Kengo Kanamaru, Hiroshi Yamagata, Hiromasa Imaishi Tags: Original Paper Source Type: research

Challenges and advances in the assessment of the disposition of antibody‐drug conjugates
Abstract Antibody‐drug conjugates (ADCs) are a rapidly growing therapeutic platform for the treatment of cancer. ADCs consist of a cytotoxic small molecule drug linked to an antibody to provide targeted delivery of the cytotoxic agent to the tumor. Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of ADCs is crucial in their design to optimize dose and regimen, to maximize efficacy and to minimize toxicity in patients. Significant progress has been made in recent years in this area, however, many fundamental questions still remain. This review discusses factors to consider while assessing the disposition ...
Source: Biopharmaceutics and Drug Disposition - June 8, 2015 Category: Drugs & Pharmacology Authors: Amrita V. Kamath, Suhasini Iyer Tags: Special Issue Article Source Type: research

Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats
ABSTRACT We evaluated the effect of hypothermia on the in vivo pharmacokinetics of midazolam (MDZ), with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with MDZ (which is metabolized mainly by CYP3A2) at 37, 32, or 28 °C. The Michaelis–Menten constant (Km) and maximum velocity (Vmax) of MDZ were estimated using the Michaelis–Menten equation. The Km of CYP3A2 MDZ remained unchanged, but the Vmax decreased at 28 °C. In rats, whose temperature was maintained at 37, 32, or 28 °C by a heat lamp or ice pack, plasma concentrations of MDZ were higher, w...
Source: Biopharmaceutics and Drug Disposition - June 3, 2015 Category: Drugs & Pharmacology Authors: Hirotaka Miyamoto, Satoshi Matsueda, Akihiro Moritsuka, Kenta Shimokawa, Haruna Hitara, Mikiro Nakashima, Hitoshi Sasaki, Shintaro Fumoto, Koyo Nishida Tags: Original Paper Source Type: research

Safety, tolerability and pharmacokinetics of 2‐pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD
This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo‐controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2‐pyridylacetic acid (2‐PAA), a major metabolite of betahistine were quantified using a validated LC‐MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0‐4 of 2...
Source: Biopharmaceutics and Drug Disposition - May 22, 2015 Category: Drugs & Pharmacology Authors: Ganesh Moorthy, Floyd Sallee, Prasad Gabbita, Frank Zemlan, Larry Sallans, Pankaj B. Desai Tags: Original Paper Source Type: research

Evaluation of food effect on the oral bioavailability of pradigastat, a diacylglycerol acyltransferase 1 inhibitor
This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - May 11, 2015 Category: Drugs & Pharmacology Authors: Surya P. Ayalasomayajula, Charles D. Meyers, Jing Yu, Mark Kagan, Ralph Matott, Parasar Pal, Tapan Majumdar, Zhenzhong Su, Anne Crissey, Sam Rebello, Gangadhar Sunkara, Jin Chen Tags: Original Paper Source Type: research

Metabolism of (‐)‐cis‐ and (‐)‐trans‐rose oxide by cytochrome P450 enzymes in human liver microsomes
This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - May 1, 2015 Category: Drugs & Pharmacology Authors: Hiroshi Nakahashi, Yuuki Yamamura, Atsushi Usami, Pramoch Rangsunvigit, Pomthong Malakul, Mitsuo Miyazawa Tags: Original Paper Source Type: research

Identification and dispositions of novel mono‐hydroxyl mefenamic acid and their potentially toxic 1‐O‐acyl‐glucuronides in vivo
ABSTRACT Mefenamic acid (MEF) is a widely prescribed non‐steroidal anti‐inflammatory drug that has been found associated with rare but severe cases of hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. Formation of protein‐reactive acylating metabolites such as 1‐O‐acyl‐MEF glucuronide (MEFG) and 3’‐hydroxymethyl‐MEF 1‐O‐acyl‐glucuronide is one proposed cause. In addition to the well‐reported 3’‐hydroxymethyl‐MEF, two mono‐hydroxyl‐MEF (OH‐MEFs) were recently identified in vitro. However, in vivo evidence and whether these OH‐MEFs would be further glucuronidated to the pot...
Source: Biopharmaceutics and Drug Disposition - May 1, 2015 Category: Drugs & Pharmacology Authors: Sophia Yui Kau Fong, Yufeng Zhang, Yin Cheong Wong, Limin Zhou, Quanbin Han, Zhong Zuo Tags: Original Paper Source Type: research

Regulation of uridine diphosphate‐glucuronosyltransferase 1A3 activity by protein phosphorylation
In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. This article is protected by copyright. All rights reserved. (Source: Biopharmaceutics and Drug Disposition)
Source: Biopharmaceutics and Drug Disposition - May 1, 2015 Category: Drugs & Pharmacology Authors: Yongsheng Xiao, Yan Yao, Huidi Jiang, Chuan Lu, Su Zeng, Lushan Yu Tags: Original Paper Source Type: research