title: Active drug transport of immunosuppressants: new insights for pharmacokinetics and pharmacodynamics.
abstract: Immunosuppressants have a narrow therapeutic index, and pharmacokinetic variability negatively affects long-term outcome of transplantation. Recently, it has become clear that active transport is a major determinant of the inter-and intraindividual variability of the pharmacokinetics and pharmacodynamics of immunosuppressants. Active transport plays a key role in (1) the poor correlation between oral doses and systemic exposure of cyclosporine, tacrolimus, sirolimus, and everolimus, (2) tissue distribution including distribution into lymphocytes, (3) hepatic and intestinal metabolism, (4) the pharmacokinetic variability of immunosuppressants after oral dosing, (5) drug-drug interactions, (6) disease-drug interactions, and (7) age, gender, and ethnicity-based differences in pharmacokinetics of immunosuppressants. Those new insights may significantly improve patient management and long-term outcome not only by reducing pharmacokinetic variability and avoidance of drug-drug interactions but also by identification of sensitive patient populations. They will also significantly impact preclinical and clinical development strategies of new immunosuppressants.
authors.affiliation: Clinical Research and Development, Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. uwe.christians@uchsc.edu
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Tobin
authors.initials: T
authors.lastname: Strom
authors.forename: Yan Ling
authors.initials: YL
authors.lastname: Zhang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Steudel
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Saskia
authors.initials: S
authors.lastname: Trump
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
mesh_terms: D000328:Adult; D001682:Biological Availability; D001693:Biological Transport, Active; D002648:Child; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D007421:Intestine, Small / Q000502:physiology*; D016377:Organ Transplantation; D010597:Pharmacogenetics; D014018:Tissue Distribution
chemical_list: D007166:Immunosuppressive Agents