Role of cytochrome P450 2C8 and 2J2 genotypes in calcineurin inhibitor-induced chronic kidney disease

Smith, Helen; Jones, J. P.; Kalhorn, Thomas F.; Farin, Federico M.; Stapleton, Patricia L.; Davis, Connie L.; Perkins, James D.; Blough, David K.; Hébert, Mary F.; Thummel, Kenneth E.; Totah, Rheem A.

doi:10.1097/fpc.0b013e32830e1e16

Cited by 54 publications

(57 citation statements)

References 38 publications

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“…Initial in vitro studies for CYP2C8*3 suggested a lower activity, 31,32 but more recent studies in healthy volunteers have repeatedly demonstrated an increased metabolizing capacity for this allele. [33][34][35][36] In contrast, CYP2C8 haplotype C 35,41 and CYP3A5*3 37 confer a reduced activity. As the polymorphisms conferring a low metabolizing capacity were associated with protection, whereas the allele with increased activity showed a higher neurotoxicity (Figure 2), and the effects of these polymorphisms were independent, we incorporated them in a single prediction model (risk alleles: rs11572080 A, rs1113129 G and rs776746 G; Table 3).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

et al. 2010

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Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele) ¼ 0.55; 95% confidence interval (CI) ¼ 0.34-0.89; P ¼ 0.014 and HR (per allele) ¼ 0.51; 95%CI ¼ 0.30-0.86; and P ¼ 0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele) ¼ 1.72; 95%CI ¼ 1.05-2.82; and P ¼ 0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR ¼ 1.64 (95% CI ¼ 1.26-2.14; P ¼ 0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

et al. 2010

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“…Those who once had acute rejection and the relapse of the primeval disease were excluded. Among all the transplantation recipients, we divided those recipients into stable group (SCr b 1.6 mg/dl) and renal dysfunction group (SCr ≥ 1.6 mg/dl) [10,11]. 27 age and gender-matched healthy subjects were included as normal controls.…”

Section: Patientsmentioning

confidence: 99%

CNI induced Th17/Treg imbalance and susceptibility to renal dysfunction in renal transplantation

Shi

Huang

et al. 2011

International Immunopharmacology

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“…EETs help to maintain blood pressure, are involved in tubular reabsorption of water and sodium transport, protect against inflammation, and the maintenance of vascular smooth muscle tone. [73][74][75] Smith et al [76] found that patients carrying one or more CY2C8*3 variant alleles have a higher risk of developing CNI-induced nephrotoxicity after liver transplantation. Possibly, decreased production of EETs in patients with the variant CYP2C8*3 allele may reduce the capacity of their kidneys to counter the vasoconstrictive effects of CNIs.…”

Section: Nephrotoxicitymentioning

confidence: 99%

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

117

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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Role of cytochrome P450 2C8 and 2J2 genotypes in calcineurin inhibitor-induced chronic kidney disease

Cited by 54 publications

References 38 publications

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

CNI induced Th17/Treg imbalance and susceptibility to renal dysfunction in renal transplantation

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

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