CYP3A4 and CYP3A5 comprise the most abundantly expressed human CYP450 activity and participate in metabolism of an estimated 40% of all marketed drugs. However, their 10-100 fold inter-individual variability in activity may have a profound effect on outcomes from drug therapy. CYP3A4*22 and CYP3A5*3 have been shown to significantly affect CYP3A4/5 activities and pharmacokinetics of various CYP3A4/5 substrates.
Dexamethasone is a widely used anti-inflammatory and immunosuppressive agent. In humans, dexamethasone is extensively metabolized by CYP3A4/5 to its major metabolite, 6-hydroxydexamethasone. Pharmacokinetic studies have revealed high inter- and intra-individual variability in dexamethasone exposure. While a few physiological and environmental factors have been identified as contributors to the variability, the contribution of genetic factors remains unclear.
The purpose of this study was to evaluate the impact of CYP3A4*22 and CYP3A5*3 polymorphisms on dexamethasone and 6-hydroxydexamethasone pharmacokinetics in cancer patients.
Pharmacokinetic and genetic data from 140 patients enrolled in multiple phase 1/2 clinical trials of anti-cancer agents were used in this retrospective study. Real time PCR and PCR-RFLP analysis were conducted on patient DNA extracted from peripheral blood cells to determine genotypes for CYP3A4*22 and CYP3A5*3. Dexamethasone and 6-hydroxydexamethasone plasma levels were quantified in 101 patients using a validated LC-MS/MS assay. Plasma samples from another 42 patients were analyzed, but dexamethasone and 6-hydroxydexamethasone were not detected. Parent drug and metabolite exposures spanned 10- and 50-fold ranges, respectively. A population nonlinear mixed effects model was developed, and the CYP3A4*22 and CYP3A5*3 genotypes were evaluated as covariates to quantify their impact on drug and metabolite disposition.
Six (6.4%) patients were determined to carry the CYP3A4*22 T allele, and 88 (93.6%) patients were homozygous for the C allele. Seventy-three (77.7%) patients were homozygous for the CYP3A5*3 G allele, and only 2 (2.1%) were homozygous for the A allele. The remaining 19 (20.2%) patients were heterozygous (AG).
Comparison of non-compartmental pharmacokinetic parameters for parent drug and metabolite revealed expected trends where CYP3A4*22 T-carriers had higher dexamethasone AUC, lower dexamethasone Cmax, and lower ratio of observed metabolite Cmax to parent exposure. For the CYP3A5*3 allele, we did not observe clear trends in the data when comparing between the three genotypes. Although our original hypothesis was that both SNPs would have a large impact on dexamethasone pharmacokinetics, based on the estimate that conversion of dexamethasone to 6-hydroxydexamethasone represents only about 40% of dexamethasone total clearance, the impact of both SNPs is likely greatest on 6-hydroxydexamethasone or on the ratio of 6-hydroxydexamethasone /dexamethasone. Population pharmacokinetic modeling revealed estimates of dexamethasone clearance and volume of distribution were 15.9 L/h and 95.9 L, respectively, which are similar to previous reports. While the limited number of patients with the CYP3A4*22 genotype who also had available pharmacokinetic data (n=4) likely contributed to the lack of significance observed in our univariate comparisons, the observed trends were consistent with hypotheses that this SNP alters dexamethasone pharmacokinetic and contributes to its inter-patient pharmacokinetic variability.
|Advisor:||Phelps, Mitch A.|
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/11(E), Dissertation Abstracts International|
|Subjects:||Pharmacology, Pharmaceutical sciences|
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