Related Experiment Video

Updated: Feb 11, 2026

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
08:59

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

Published on: December 3, 2020

8.7K

Quantitative Analysis of Complex Drug-Drug Interactions between Cerivastatin and Metabolism/Transport Inhibitors

Yoshiaki Yao1, Kota Toshimoto1, Soo-Jin Kim1

  • 1Analysis & Pharmacokinetics Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (Y.Y.), and Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Kanagawa, Japan (K.T., S.K., T.Y., Y.S.).

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|May 2, 2018
PubMed

Insights

Physiologically based pharmacokinetic models accurately predicted drug-drug interactions between cerivastatin and cyclosporine A or gemfibrozil. This approach aids in understanding and predicting cerivastatin interactions, crucial for patient safety.

Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Computational Biology and Modeling

Background:

  • Cerivastatin withdrawal due to rhabdomyolysis highlighted safety concerns.
  • Coadministration with cyclosporine A or gemfibrozil increases cerivastatin levels.
  • Cyclosporine A and gemfibrozil inhibit key transporters (OATP1B1) and enzymes (CYP3A4, CYP2C8).

Purpose of the Study:

  • To model cerivastatin drug-drug interactions (DDIs) with cyclosporine A and gemfibrozil using physiologically based pharmacokinetic (PBPK) models.
  • To evaluate the quantitative analysis of these DDIs via a bottom-up approach.

Main Methods:

  • Construction of PBPK models for cerivastatin and gemfibrozil/gemfibrozil glucuronide.
  • Optimization of drug-dependent parameters using the Cluster Newton Method.
  • Simulation of DDIs using established PBPK models and in vitro inhibition data.

Main Results:

  • PBPK models accurately described cerivastatin and gemfibrozil concentration-time profiles.
  • Initial DDI simulations underestimated observed clinical data.
  • Sensitivity analyses identified optimal in vitro parameter sets, leading to accurate DDI reproduction.

Conclusions:

  • Physiologically based pharmacokinetic models can adequately describe clinical cerivastatin DDIs using a bottom-up approach.
  • The developed modeling approach is applicable for predicting other transporter- and enzyme-mediated DDIs.

More Related Videos

The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport13:17

The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport

Published on: March 6, 2015

29.7K
Use of Rabbit Eyes in Pharmacokinetic Studies of Intraocular Drugs10:02

Use of Rabbit Eyes in Pharmacokinetic Studies of Intraocular Drugs

Published on: July 23, 2016

33.4K

Related Concept Videos

Pharmacokinetics: Drug–Drug Interactions01:25

Pharmacokinetics: Drug–Drug Interactions

Drug interactions occur when the pharmacological effect of one drug is altered by another substance, either enhancing or diminishing its activity. The drug whose activity is altered is known as the object drug, and the substance causing the alteration is called the agent drug or the precipitant. The net effects of these interactions are mostly undesirable, leading to decreased effectiveness or increased adverse effects. In rare cases, interactions can be beneficial, such as the enhanced...
462
Pharmacokinetics: Drug–Food and Drug–Viral Interactions01:26

Pharmacokinetics: Drug–Food and Drug–Viral Interactions

A drug interaction occurs when the concurrent use of another drug, food, or an external substance alters the pharmacological activity of a drug. This interaction can modify the action of the original drug, affecting its effectiveness and safety.Drug–food interactions are significant as they impact drug absorption, metabolism, and excretion. For example, grapefruit juice is a well-known disruptor of drug metabolism. It inhibits the cytochrome P450 3A4 enzyme, crucial for the metabolism of...
262
Pharmacokinetics in Pediatric Patients: Drug Metabolism01:24

Pharmacokinetics in Pediatric Patients: Drug Metabolism

In pediatric care, understanding the nuances of hepatic drug metabolism is crucial, as it significantly differs from that of adults. This divergence is primarily due to the developmental stage of drug-metabolizing enzymes, which affects how medications are processed in the body. In neonates, for instance, the activity of Phase I enzymes—critical for the initial breakdown of drugs—is markedly reduced, functioning at just 20–40% of the levels seen in adults. This reduction poses...
245
Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug01:14

Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug

In pharmacotherapy, monitoring drug concentrations is paramount, especially for drugs whose therapeutic effects hinge on both the active compound and its metabolite. Hepatic impairment profoundly influences drug potency by altering liver function. If the drug is more potent than its metabolite, impaired liver function amplifies drug activity due to elevated drug concentration levels. Conversely, if the metabolite holds greater potency, diminished liver function diminishes drug activity by...
234
Pharmacokinetics in Geriatric Patients: Effect of Age on Drug Metabolism01:18

Pharmacokinetics in Geriatric Patients: Effect of Age on Drug Metabolism

Geriatric patients show significant variation in how their bodies process medications, which can change how effective and safe treatments are. The liver is the primary organ where drug metabolism occurs, involving two main types of chemical reactions: phase I and II. Phase I metabolism is driven by the cytochrome P450 enzyme system, which includes key types such as CYP3A, CYP2D6, and CYP2C9. Research indicates that while aging doesn't notably alter the levels or activity of these enzymes, it...
223
Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion01:20

Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion

Drug metabolism, a critical process in the liver, involves two primary phases: Phase I reactions and Phase II conjugation. Obesity introduces significant alterations in this metabolic process, primarily due to fatty infiltration of the liver, leading to conditions such as nonalcoholic fatty liver disease (NAFLD). This condition can modify the activities of both Phase I and II enzymes, impacting how drugs are metabolized in obese patients.Phase I metabolism sees variable effects across...
194