Journal ArticleDOI
Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus
Dennis A. Hesselink,Ron H.N. van Schaik,Ilse P. van der Heiden,Marloes van der Werf,Peter J. H. Smak Gregoor,Jan Lindemans,Willem Weimar,Teun van Gelder +7 more
TLDR
The calcineurin inhibitors cyclosporine (INN, ciclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics.Abstract:
Background
The calcineurin inhibitors cyclosporine (INN, ciclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P-glycoprotein, encoded by MDR-1.
Objective
Our objective was to determine the role of genetic polymorphisms in CYP3A4, CYP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics.
Methods
Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype.
Results
Tacrolimus dose-adjusted trough levels were higher in CYP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/kg (P < .0001, Mann-Whitney test). CYP3A4*1B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type (*1/*1) genotype (n = 54): median and range, 57 (40-163) ng/mL per mg/kg versus 89 (34-398) ng/mL per mg/kg) (P = .003, Mann-Whitney test). No evidence was found supporting a role for the MDR-1 C3435T polymorphism in tacrolimus dose requirement. None of the polymorphisms studied correlated with cyclosporine dose-adjusted predose concentrations.
Conclusion
As a group, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 allele carriers, whereas CYP3A4*1B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes.
Clinical Pharmacology & Therapeutics (2003) 74, 245–254; doi: 10.1016/S0009-9236(03)00168-1read more
Citations
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Journal ArticleDOI
Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation
TL;DR: Recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s are reviewed.
Journal ArticleDOI
Calcineurin Inhibitor Nephrotoxicity
TL;DR: The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cycloporine or tacolimus could be more important than systemic exposure.
Journal ArticleDOI
Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects
TL;DR: It is concluded that the pharmacogenetic knowledge regarding CYP polymorphism now developed to a stage where it can be implemented in drug development and in clinical routine for specific drug treatments, thereby improving the drug response and reducing costs for drug treatment.
Journal ArticleDOI
Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation.
TL;DR: Critics have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within ‘acceptable’ ranges, and controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring.
Journal ArticleDOI
Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation
Ulrich M. Zanger,Ulrich M. Zanger,Miia Turpeinen,Miia Turpeinen,Miia Turpeinen,Kathrin Klein,Kathrin Klein,Matthias Schwab,Matthias Schwab +8 more
TL;DR: The elimination routes for the 200 drugs that are sold most often by prescription count in the United States were investigated and Clinically well-established polymorphic CYPs were involved in the metabolism of approximately half of those drugs, including NSAIDs metabolized mainly by CYP2C9, proton-pump inhibitors metabolized by CYD2C19, and beta blockers and several antipsychotics and antidepressants metabolizing by CYB2D6.
References
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Journal ArticleDOI
Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo
Sven Hoffmeyer,Oliver Burk,O. von Richter,H. P. Arnold,Jürgen Brockmöller,Andreas Johne,Ingolf Cascorbi,Thomas Gerloff,Ivar Roots,Eichelbaum Michel,Ulrich Brinkmann +10 more
TL;DR: A significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function is observed and this polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of M DR-1.
Journal ArticleDOI
Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.
Peter M. Kuehl,Jiong Zhang,Yvonne S. Lin,Jatinder K. Lamba,Mahfoud Assem,John D. Schuetz,Paul B. Watkins,Ann K. Daly,Steven A. Wrighton,Stephen D. Hall,Patrick Maurel,Mary V. Relling,Cynthia Brimer,Kazuto Yasuda,Raman Venkataramanan,Stephen C. Strom,Kenneth E. Thummel,Mark S. Boguski,Erin G. Schuetz +18 more
TL;DR: CYP3A5 was more frequently expressed in livers of African Americans than in those of Caucasians, and may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.
Journal ArticleDOI
Clinical Pharmacokinetics of Tacrolimus
Raman Venkataramanan,Arun Swaminathan,Tata Prasad,Ashok Jain,Sheila Zuckerman,Vijay Warty,John McMichael,J. Lever,Gilbert J. Burckart,Thomas E. Starzl +9 more
TL;DR: Monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design because of this variability, the narrow therapeutic index of tacolimus, and the potential for several drug interactions.
Journal ArticleDOI
Role of intestinal P‐glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine
Kenneth S. Lown,Kenneth S. Lown,Robert R. Mayo,Robert R. Mayo,Alan B. Leichtman,Alan B. Leichtman,Hsiu Ling Hsiao,Hsiu Ling Hsiao,D. Kim Turgeon,D. Kim Turgeon,Phyllissa Schmiedlin-Ren,Phyllissa Schmiedlin-Ren,Morton B. Brown,Morton B. Brown,Wensheng Guo,Wensheng Guo,Stephen J. Rossi,Stephen J. Rossi,Leslie Z. Benet,Leslie Z. Benet,Paul B. Watkins,Paul B. Watkins +21 more
TL;DR: It is concluded that intestinal P‐glycoprotein plays a significant role in the first‐pass elimination of cyclosporine, presumably by being a rate‐limiting step in absorption.
Journal ArticleDOI
Human P-glycoprotein transports cyclosporin A and FK506.
TL;DR: Results indicate that P-glycoprotein transports the immunosuppressive agents cyclosporin A and FK506.
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