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. 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). 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. 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. Association of ABCB1 genotypes and docetaxel-mediated peripheral neuropathy and neutropenia: Patients with AIPC treated with docetaxel alone (n=23), or docetaxel and thalidomide (n=50), were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm. The data were then compared to duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel. For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C haplotype had improved overall survival after treatment (P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival (P = 0.045). Among both treatment arms together, individuals carrying the 2677GG genotype also had a significantly longer time to neuropathy (P = 0.035). Finally, there was a strong trend towards patients carrying the 2677TT-3435TT diplotype having higher grades of neutropenia (P = 0.053). The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes. Association of CYP1B1*3 with docetaxel efficacy, and a mechanistic determination of the gene-drug interaction: Using a SNP association study in 52 men with prostate cancer receiving docetaxel, we found that individuals carrying two copies of the CY1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared to individuals carrying at least one copy of the CYP1B1*1 allele (30.6 vs 12.8 months; P = 0.006). The association between CYP1B1*3 and response to therapy was not observed in similar subjects receiving non-taxane-based therapy (P = 0.18). The systemic clearance of docetaxel was also unrelated to CYP1B1 genotype status (P = 0.39), indicating that the association of CYP1B1*3 with clinical response is not due to docetaxel metabolism. To explain these results, we hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. We therefore conducted tubulin polymerization experiments with taxanes in the presence or absence of certain CYP1B1 estrogen metabolites that are known to bind to nucleophilic sites in proteins and DNA, that revealed the primary estrogen metabolite of CYP1B1, 4-hydroxyestradiol, when oxidized to estradiol-3,4-quinone strongly inhibits tubulin polymerization. The 4-hydroxyestradiol is also formed more readily by the protein encoded by the CYP1B1*3 allele, validating further our data in patients. Furthermore, estradiol-3,4-quinone reacted in vitro with docetaxel to form the 4-OH estradiol-docetaxel adduct. This pilot study provides evidence that CYP1B1*3 may be an important marker for estimating docetaxel efficacy in patients with prostate cancer. This link is likely associated with CYP1B1*3 genotype-dependent estrogen metabolism. Pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer using the Affymetrix DMET-T 1.0 genotyping platform: We pilot tested the new Affymetrix Drug Metabolizing Enzymes and Transporter (DME-T) panel in an exploratory study of doctaxel and thalidomide. The DME-T panel tests for 1,243 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. DNA samples from patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DME-T platform. Patients response was determined using the PSA Working Group consensus criteria. Toxicities were identified the CTEP/NCI-CTCAE (version 2.0). Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. Genetic polymorphisms were then related to clinical response and toxicity measures. Ten SNPs in three genes were associated with response to therapy: PPAR-delta, SULT1C2, and CHST3. Three genes were identified in association with docetaxel toxicities: UGT1A1, UGT1A9, and CYP2A7. SNPs in CYP2B6, ABCC1, and ABCC6 were associated with toxicities from thalidomide. We identified nine genes in which SNPs were associated with clinical response and toxicity to treatment using docetaxel and thalidomide in patients with metastatic, androgen independent prostate cancer. These results highlight the important role that non-CYP450, phase II drug metabolizing enzymes as well as drug transporters may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. 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 CY [summary truncated at 7800 characters]
Showing the most recent 10 out of 32 publications
