Advanced knowledge in drug metabolism and pharmacokinetics
Authors: Ai-Ming Yu, Xiao-bo Zhong
Journal: Acta Pharmaceutica Sinica B (2016)

Acta Pharmaceutica Sinica B 2016;6(5):361–362 Chinese Pharmaceutical Association Institute of Materia Medica, Chinese Academy of Medical Sciences Acta Pharmaceutica Sinica B www.elsevier.com/locate/apsb www.sciencedirect.com EDITORIAL Advanced knowledge in drug metabolism and pharmacokinetics Drug metabolism and transport in human organs, such as in the liver, intestine, and kidney, control the concentrations of a drug and its metabolites in the circulating system and target organs in a certain period of time following drug administration. The pharma- cokinetic properties will consequently determine therapeutic efﬁ- cacy and inﬂuence toxicological effects. Changes of drug metabolism and pharmacokinetics may result in signiﬁcant inter- individual variations in therapeutic efﬁcacy and adverse drug reactions. Therefore, understanding drug metabolism and pharma- cokinetic properties is essential for drug development and clinical therapy. Growing researches in these areas also promote the development of novel approaches to implementation of persona- lized medicine or precision medicine. This special issue consists of a set of original research and review articles providing recently- gained information in these areas. As the guest Editors, we would like to appreciate the journal for providing us the opportunity to share the information and thank all authors for their contributions. Cytochrome P450 (CYP or P450) enzymes are the major super- family of phase I drug-metabolizing enzymes. Extensive studies have demonstrated the impact of hepatic P450 functions and regulation on drug metabolism and responses. However, intestinal P450-mediated drug metabolism is an important factor dictating ﬁrst-pass metabolism and oral bioavailability. Fang Xie and colleagues provide an updated review on the role of intestinal P450 enzymes in drug disposition (see a story for the front cover) 1 . The utility of genetically engineered mouse models, which target the P450-reductase (CPR) on speciﬁc tissues, in deﬁning the contribution of intestinal and hepatic P450s to drug metabolism and pharmacokinetics is also discussed. CYP2B6 is one isoform among P450 superfamily and it metabolizes 2%–10% of clinically-used drugs. William Hedrich and colleagues present an overview on key players in the regulation of CYP2B6 expression and functions and highlight recent advanced knowledge in CYP2B6- mediated drug–drug interactions 2 . Transporters are another super- family of proteins involved in drug absorption, distribution, and elimination. In particular, renal drug transporters play an important role in secretion and reabsorption of drugs in the kidney. Jia Yin and Joanne Wang give a comprehensive review on the functional characteristics of major human renal drug transporters and their involvement in clinically signiﬁcant pharmacokinetic drug–drug interactions (see a story for the back cover) 3 . Several key transcription factors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), hepatocyte nuclear factor 4 alpha (HNF4α), and estrogen receptor (ER), have been demonstrated to play important roles in the regulation of gene expression of drug-metabolizing enzymes and transporters. Several research and review articles have focused on novel aspects of these transcription factors in the regulation of drug metabolism and transport gene expression. Jiong Yan and Wen Xie describe a historical overview on the discovery of PXR and CAR as xenobiotic receptors 4 . Trent Brewer and Taosheng Chen discuss several PXR protein variants and their impact on drug metabolism and therapeutic responses 5 . Shinhee Park and colleagues characterize gene expression of CAR-targeted drug-metabolizing enzymes and transporters in mouse intestine 6 . Hong Lu gives a comprehensive review on HNF4α-controlled gene expression and crosstalks of HNF4α with diverse extracellular and intracellular signaling path- ways in the modulation of hepatic drug metabolism and lipid homeostasis 7 . Yan Zhu and colleagues provide a review on the critical roles of FXR in the control of bile acid homeostasis and illustrate the molecular mechanisms behind dysregulation of bile acids in promoting liver injury and nonalcoholic fatty liver disease 8 . Lai Peng and colleagues determine the role of FXR in establishment of ontogeny of phase I drug-metabolizing enzyme gene expression in mouse liver 9 . Sung-joon Cho and colleagues demonstrate that upregulation of UGT1A9 gene expression by estradiol is a transcrip- tional response to the activation of ERα receptor 10 . Pharmacokinetics/pharmacodynamics (PK/PD) modeling and simulation offer quantitative understanding of drug exposure and response, guide the selection of dose and dose regimen, and predict interindividual variability towards precision medicine. Xiaomei Zhuang and Chuang Lu provide an overview on the concept and methodology of physiologically based pharmacoki- netic (PBPK) modeling 11 . Case studies are presented to illustrate how PBPK modeling and simulation may beneﬁt drug discovery Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. http://dx.doi.org/10.1016/j.apsb.2016.08.003 2211-3835 & 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).