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XK469 (NSC 697887) is a selective topoisomerase II inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (=−0.32, P=0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (=0.18, P=0.20). Four other AOX1SNPs were associated with clearance (P=0.01–0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.

ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751.

High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor. Thus, we hypothesized that the variability can be explained by genetic variants of the uridine 5′-diphosphate-glucuronosyltransferases (UGTs) involved in vorinostat metabolism. Baculosomes expressing human UGTs and 52 human liver microsomes were screened for vorinostat glucuronidation activity to identify the potential enzymes and functional variants. UGT2B17 had the largest activity. Human liver microsomes with at least one copy of UGT2B17 showed significantly greater enzymatic activity than those with UGT2B17 null genotype (P<0.004). UGT2B17 plays an important role in vorinostat hepatic glucuronidation and the gene deletion polymorphism may influence vorinostat biotransformation and clearance. The clinical impact of this UGT2B17 genetic variant on vorinostat metabolism and drug effect is unknown.

UDP-glucuronosyltransferase 2B7 (UGT2B7) plays a central role in the liver-mediated biotransformation of endogenous and exogenous compounds. The genetic basis of interindividual variability in UGT2B7 function is unknown. This study aimed to discover novel gene variants of functional significance.

UGT1A1 is induced by phenobarbital. We investigated whether three common UGT1A1variants are associated with the variability in UGT1A1inducibility. Human hepatocytes were incubated with 2 mM phenobarbital for 2 and 6 days followed by 5 μM SN-38 (1 h), a UGT1A1 probe. SN-38 glucuronidation in the cell media was measured by high-performance liquid chromatography. Three UGT1A1promoter variants −53(TA)6>7, −3156G>A and −3279T>G were genotyped. Significant induction of UGT1A1 catalytic activity was observed in 82 and 100 of the cultures treated with phenobarbital for 2 days (median fold-induction1.6, range 1.3–2.8; n28) and 6 days (median fold-induction2.8, range 1.6–6.4; n16), respectively. After 2 days of treatment, a negative correlation was observed between the UGT1A1 basal activities and the fold-induction (Spearman r−0.52, P<0.005). By contrast, the UGT1A1 activities in the basal and induced states were highly correlated (Spearman r0.95, P<0.0001). Similar results were observed after 6 days of treatment. The allele frequencies were not significantly different between induced (n22) and non-induced preparations (n6) (P>0.05). The fold-induction was not associated with any variants (P>0.05). The basal and induced activities were correlated with −53(TA)6>7(and with −3156G>A due to almost complete linkage with the −53 indel) (P0.001). No association was found with the −3279T>G single nucleotide polymorphism (P>0.05). The indel at −53 affects the basal phenotype and appears to limit the hepatocyte capability of maximal induction after phenobarbital. However, variants at −53, −3156 and −3279 are not associated with variability in UGT1A1inducibility.