Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the and genes

Hesselink, Dennis A.; Gelder, Teun van; Schaik, Ron H.N. van; Balk, A. H. M. M.; Heiden, Ilse P. van der; Dam, Thea van; Werf, M. van der; Weimar, Willem; Mathôt, Ron A. A.

doi:10.1016/j.clpt.2004.08.022

Cited by 159 publications

(118 citation statements)

References 45 publications

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“…In the present study, CYP3A4*1B decreased the inducible thiotepa clearance. Other authors have shown that CYP3A4*1B caused a modest decrease in systemic midazolam [38] and ciclosporin clearance [39,40], whereas others did not find an effect [41,42].…”

Section: Discussionmentioning

confidence: 96%

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Ekhart

Doodeman

Rodenhuis

et al. 2008

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Thiotepa is metabolized by oxidative desulphuration by the cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 to tepa. • Furthermore, thiotepa and tepa are conjugated to glutathione, which is catalysed by glutathione S-transferase (GST) isoenzymes A1-1 and P1-1. • Polymorphisms in these enzymes could influence exposure to thiotepa and tepa.• Little is known about the influence of polymorphisms in these enzymes on the pharmacokinetics of thiotepa and tepa. WHAT THIS STUDY ADDS• The presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics.• We show that probably only the GSTP1 C341T variant allele influences thiotepa exposure to a clinically relevant extent. AIMSThiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of thiotepa and tepa. METHODSWhite patients (n = 124) received a high-dose regimen consisting of cyclophosphamide, thiotepa and carboplatin as intravenous infusions. Genomic DNA was analysed using polymerase chain reaction and sequencing. Plasma concentrations of thiotepa and tepa were determined using validated GC and LC-MS/MS methods. Relations between allelic variants and elimination pharmacokinetic parameters were evaluated using nonlinear mixed effects modelling (NONMEM). RESULTSThe polymorphisms CYP2B6 C1459T, CYP3A4*1B, CYP3A5*3, GSTA1 (C-69T, G-52A) and GSTP1 C341T had a significant effect on clearance of thiotepa or tepa. Although significant, most effects were generally not large. Clearance of thiotepa and tepa was predominantly affected by GSTP1 C341T polymorphism, which had a frequency of 9.3%. This polymorphism increased non-inducible thiotepa clearance by 52% [95% confidence interval (CI) 41, 64, P < 0.001] and decreased tepa clearance by 32% (95% CI 29, 35, P < 0.001) in heterozygous patients, which resulted in an increase in combined exposure to thiotepa and tepa of 45% in homozygous patients. CONCLUSIONSThis study indicates that the presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Patients homozygous for the GSTP1 C341T allele may have enhanced exposure to thiotepa and tepa.

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Section: Discussionmentioning

confidence: 96%

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Ekhart

Doodeman

Rodenhuis

et al. 2008

Brit J Clinical Pharma

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“…241); the impact of single nucleotide polymorphisms in ABCB1 is less clear. The largest cohort studies did not demonstrate an association of ABCB1 polymorphisms with cyclosporine pharmacokinetics (238,(242)(243)(244), and the effects of ABCB1 polymorphisms on tacrolimus pharmacokinetics are not consistent (238 -240,245,246). This demonstrates that ABCB1 variants, at maximum, explain tacrolimus pharmacokinetics to a limited degree.…”

Section: Systemic Levels Of Cyclosporine and Tacrolimusmentioning

confidence: 99%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,263

1,000

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. 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 cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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“…21,42,[42][43][44][45][46][47][48][49][50][51] A further study has shown that the pharmacodynamic effects of cyclosporine on peripheral blood mononuclear cells were affected by the level of PGP expression, but not by the ABCB1 3435C4T genotype. 52 There was also no correlation between the 3435C4T genotype and PGP expression at the protein level in this study.…”

Section: Immunosuppressive Drugsmentioning

confidence: 99%

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

et al. 2006

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The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

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Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the and genes

Cited by 159 publications

References 45 publications

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

Calcineurin Inhibitor Nephrotoxicity

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

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