Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib: Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib. Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d. Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild-type ABCG2 (P = .028). However, pharmacokinetic parameters of imatinib in vivo were not statistically significantly different in 16 patients who were heterozygous for ABCG2 421C>A compared with 66 patients carrying the wild-type sequence (P = .479). The apparent oral clearance of imatinib was potentially reduced in individuals with at least 1 CYP2D6*4 allele (median, 7.78 versus 10.6 L/h; P = .0695). Pharmacokinetic parameters were not related to any of the other multiple-variant genotypes (P >or= .230), possibly because of the low allele frequencies. This study indicates that common genetic variants in the evaluated genes have only a limited impact on the pharmacokinetics of imatinib. Further investigation is required to quantitatively assess the clinical significance of homozygous variant ABCG2 and CYP2D6 genotypes in patients treated with imatinib.Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia: We evaluated the relationships between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-induced toxicity and pharmacokinetics. Twenty-six patients were assessable for pharmacogenetics and pharmacokinetics, 22 for neurotoxicity and 18 for myelotoxicity. Patients carrying two reference alleles for the ABCB1 3435C>T polymorphism trended toward a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P=0.09). Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir (P=0.02). Neither polymorphism correlated with paclitaxel pharmacokinetics. This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.Impact of ABCB1 allelic variants on QTc interval prolongation: We evaluated the associations of ABCB1 and CYP3A5 genotypes with the pharmacokinetics and pharmacodynamics of romidepsin. Romidepsin was administered to 45 patients as a 4-hour infusion at a dose of 14 or 18 mg/m2. Phenotypic parameters including change in the baseline-corrected QTc interval at 4 hours (QTc), and plasma clearance were analyzed. An independent analysis was conducted in a separate cohort of 29 patients receiving romidepsin at doses ranging from 12.7 to 24.3 mg/m2. In the initial analysis, individuals carrying the ABCB1 2677TT genotype had a lower QTc (P =.0046) than others, while patients with a greater number of reference alleles at the 2677G>T/A and 3435C>T loci experienced a higher QTc (P = .011). In the confirmatory analysis, individuals carrying the 2677GT or TT genotypes had a lower QTc (P = .015), while the diplotype at the 2677 and 3435 loci showed a trend toward altered ?QTc (P = .07). None of the ABCB1 and CYP3A5 allelic variants were associated with the systemic clearance of romidepsin: From these experiments, we conclude that QT interval prolongation associated with romidepsin treatment appears to be linked to ABCB1 variants.
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