title: Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport.
abstract: BACKGROUND
  Mechanistic understanding of the metabolism-transport interplay assumes great importance in pharmaceutical fields because the knowledge can help to interpret drug/xenobiotic metabolism and disposition studies as well as the drug-drug interactions in vivo. About 10 years ago, it started to recognize that cellular phase II metabolism is strongly influenced by the excretion (efflux transport) of generated metabolites, a kinetic phenomenon termed "phase II metabolism-transport interplay". This interplay is believed to have significant effects on the pharmacokinetics (bioavailability) of drugs/chemicals undergoing phase II metabolism.
  
  
  METHODS
  In this article, we review the studies investigating the phase II metabolism-transport interplay using cell models, perfused rat intestine, and intact rats. The potential confounding factors in exploring such interplay is also summarized. Moreover, the mechanism underlying the phase II metabolism-transport interplay is discussed.
  
  
  RESULTS
  Various studies with engineered cells and rodents have demonstrated that there is an interaction (interplay) between phase II enzymes and efflux transporters. This type of interplay mainly refers to the dependence of phase II (conjugative) metabolism on the activities of efflux transporters. In general, inhibiting efflux transporters or decreasing their expression causes the reductions in metabolite excretion, apparent excretion clearance (CLapp) and total metabolism (fmet), as well as an increase in the intracellular level of metabolite (Ci). The deconjugation mediated by hydrolase (acting as a "bridge") is essential for the interplay to play out based on pharmacokinetic modeling/simulations, cell and animal studies. The hydrolases bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof (a bridging effect). Without the bridge, metabolite formation is independent on its downstream process excretion, thus impact of metabolite excretion on its formation is impossible.
  
  
  CONCLUSIONS
  Deconjugation (mediated by hydrolases) plays an essential role in the conjugation-transport interplay.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Huijie
authors.initials: H
authors.lastname: Xing
authors.forename: Mengjing
authors.initials: M
authors.lastname: Zhao
authors.forename: Danyi
authors.initials: D
authors.lastname: Lu
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Li
authors.affiliation: International Ocular Surface Research Center and Institute of Ophthalmology, Jinan University Medical School, Guangzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Dong
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Jinan University, 601 Huangpu Road West, Guangzhou, Guangdong 510632, China.
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations; D014453:Glucuronosyltransferase; D015239:Arylsulfotransferase
keywords: Arylsulfatase; SULT; UGT; bioavailability; interplay; phase II metabolism