ABSTRACT
Cytochrome P450s (CYP450) is a superfamily of phase I metabolic enzymes, which participates in more than 90% of drug oxidation. The induction or inhibition of CYP450s is the main mechanism of drug-drug interaction. In recent years, in vitro metabolism studies conducted through isolated organs, cells, or enzyme systems have developed rapidly, due to their precision and simplicity. Therefore, profiles of the in vitro metabolism studies of traditional Chinese medicines can infer the possible metabolic pathways of drugs, predict the potential drug interactions, and may enhance the rational use of drugs in clinic. This article reviews the in vitro inhibitory effects of traditional Chinese medicine, ingredients, and extracts on the activities of CYP450 enzymes in the liver microsomes, which can provide a reference for further researches on the interaction between Chinese medicine and chemical medicine.
ABSTRACT
Gastric pH is an important factor that affects drug absorption, as gastric pH may lead to lower bioavailability, especially for weak-base drugs. Acid-reducing agents (ARAs) such as antacids, histamine-2 receptor antagonists, and proton pump inhibitors, are susceptible to drug-drug interactions (DDIs), potentially resulting in the loss of efficacy. Physiologically based pharmacokinetic (PBPK) modeling is an important tool for the evaluation of oral drug-drug interactions and the most commonly used models include the advanced comparative absorption and transport (ACAT) model and the advanced dissolution, absorption and metabolism (ADAM) model. These models can be used for adjustment of the dosage regimen and the screening of candidate drugs in drug development by simulating the change of gastric pH to predict the change in drug absorption. This review summarizes the theoretical basis, the most common PBPK models used to predict drug absorption, and the effects of different kinds of ARAs drugs on gastric pH. Some successful applications of PBPK modeling in predicting the effects of gastric pH on drug absorption are also presented.
ABSTRACT
Physiologically based pharmacokinetic (PBPK) modeling is an important tool to predict pharmacokinetic or pharmacodynamic profiles in special populations, especially in children and infants where designing and conducting clinical studies is difficult. The application of PBPK modeling can effectively promote the development of pediatric drugs and their clinical use. At present, PBPK modeling of pediatric populations is mainly applied in clinical trial design, drug-drug interaction (DDI) risk assessment, and dose selection in children. This review discusses the advantages of PBPK modeling in pediatric drug research and summarizes how to extrapolate a PBPK model from adults to children. The theoretical basis for pediatric PBPK models, the modelling process and important physiological parameters during the modeling process are introduced. Some successful applications of PBPK modeling in pediatric drug research and development are also presented. This review also analyzes the current limitations and future directions of pediatric PBPK modeling.
ABSTRACT
The goal of this work was to establish a population pharmacokinetics (PPK) model of tacrolimus in idiopathic membranous nephropathy (IMN) patients and to identify potential covariates that influence pharmacokinetic of tacrolimus. A total of 610 data points on the blood concentration of tacrolimus were collected from 96 IMN patients in routine clinical settings. Nonlinear mixed-effect modeling (NONMEM) was used to investigate the effects of CYP3A5 genotype, age, gender, weight, laboratory tests and co-therapy medications on the pharmacokinetic of tacrolimus. The PPK model was evaluated by the goodness-of-fit (GOT), bootstrap and prediction corrected visual predictive check (pc-VPC). The pharmacokinetic of tacrolimus was described by a one-compartment model. The apparent clearance (CL/F) of CYP3A5*1/*3 and *1/*1 were 1.57 and 1.86 times of that of *3/*3, respectively. The CL/F of tacrolimus was 73.6% in patients undergoing co-therapy with Wuzhi capsules, and 1.2 times than that of the patients undergoing co-therapy with Jinshuibao capsules. The evaluation of the model shows that the model is stable and has satisfactory predictive performance. The clinical trial was approved by the Society of Ethics and conducted in Binzhou Medical University Hospital. The established PPK model can describe the pharmacokinetic characteristics of tacrolimus in Chinese patients with IMN, and can facilitate individualized therapy with tacrolimus.