title: Role of enterohepatic recirculation in drug disposition: cooperation and complications.
abstract: Enterohepatic recirculation (EHC) concerns many physiological processes and notably affects pharmacokinetic parameters such as plasma half-life and AUC as well as estimates of bioavailability of drugs. Also, EHC plays a detrimental role as the compounds/drugs are allowed to recycle. An in-depth comprehension of this phenomenon and its consequences on the pharmacological effects of affected drugs is important and decisive in the design and development of new candidate drugs. EHC of a compound/drug occurs by biliary excretion and intestinal reabsorption, sometimes with hepatic conjugation and intestinal deconjugation. EHC leads to prolonged elimination half-life of the drugs, altered pharmacokinetics and pharmacodynamics. Study of the EHC of any drug is complicated due to unavailability of the apposite model, sophisticated procedures and ethical concerns. Different in vitro and in vivo methods for studies in experimental animals and humans have been devised, each having its own merits and demerits. Involvement of the different transporters in biliary excretion, intra- and inter-species, pathological and biochemical variabilities obscure the study of the phenomenon. Modeling of drugs undergoing EHC has always been intricate and exigent models have been exploited to interpret the pharmacokinetic profiles of drugs witnessing multiple peaks due to EHC. Here, we critically appraise the mechanisms of bile formation, factors affecting biliary drug elimination, methods to estimate biliary excretion of drugs, EHC, multiple peak phenomenon and its modeling.
authors.affiliation: a Department of Pharmaceutics , National Institute of Pharmaceutical Education and Research (NIPER) , Raebareli , India ;|b Pharmacokinetics & Metabolism Division , CSIR-Central Drug Research Institute , Lucknow , India ;
authors.forename: Mohd Yaseen
authors.initials: MY
authors.lastname: Malik
authors.affiliation: b Pharmacokinetics & Metabolism Division , CSIR-Central Drug Research Institute , Lucknow , India ;|c Academy of Scientific and Innovative Research , New Delhi , India ;
authors.forename: Swati
authors.initials: S
authors.lastname: Jaiswal
authors.affiliation: b Pharmacokinetics & Metabolism Division , CSIR-Central Drug Research Institute , Lucknow , India ;|c Academy of Scientific and Innovative Research , New Delhi , India ;|d Department of Pharmaceutics and Drug Delivery, School of Pharmacy , The University of Mississippi , Oxford , USA.
authors.forename: Abhisheak
authors.initials: A
authors.lastname: Sharma
authors.affiliation: b Pharmacokinetics & Metabolism Division , CSIR-Central Drug Research Institute , Lucknow , India ;|c Academy of Scientific and Innovative Research , New Delhi , India ;
authors.forename: Mahendra
authors.initials: M
authors.lastname: Shukla
authors.affiliation: b Pharmacokinetics & Metabolism Division , CSIR-Central Drug Research Institute , Lucknow , India ;|c Academy of Scientific and Innovative Research , New Delhi , India ;
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D001682:Biological Availability; D004764:Enterohepatic Circulation / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations
keywords: Biliary excretion; bioavailability; multiple peaks; pharmacokinetic modeling