Innocenti_2004_J.Clin.Oncol_22_2010

2010 Background: CPT-11 is oxidized to inactivated metabolites (including APC) by CYP3A enzymes and activated to SN-38 by carboxylesterase-2 (CES-2). SN-38 is inactivated to it glucuronide (SN-38G) by UGT1A1 and UGT1A9. Other enzymes and ABC transporters are involved in pathways of CPT-11 disposition. We had previously measured the plasma PK of patients treated with CPT-11 and analyzed the correlation with UGT1A1 variants. This study aims to generate hypotheses regarding the phenotypic effects of variation in other drug metabolizing and transporter genes.
METHODS: CPT-11, SN-38, and SN-38G AUCs were measured after a 350 mg/m2 IV dose in 64 adults with refractory solid tumors as part of a pharmacogenetic study. Genotyping of common variants (q>0.10) was performed for the following genes (number of variants in parenthesis): CES-2 (n=2), ABCC1 (n=7), ABCC2 (n=6), and ABCB1 (n=8). CYP3A4*1B, CYP3A5*3, UGT1A9 -11810T/9T and HNF1 79A>C were also typed.
RESULTS: The synonymous 3972T>C variant in ABCC2 was correlated with CPT-11 AUC (p=0.02), APC AUC (p<0.0001) and APC/CPT-11 AUC ratios (p<0.0001, ANOVA). For SN-38 and SN-38G AUC, the correlation with 3972T>C was analyzed in the subset of patients with 6/6 and 6/7 UGT1A1 genotype (n=54) to minimize the confounding effect of 7/7. SN-38G and SN-38G/SN-38 AUC ratios were correlated with 3972T>C (p<=0.001, ANOVA). No significant correlation was observed between SN-38 AUC and 3972T>C (p=0.9). Other gene variants showed either no or borderline statistical significance in the ANOVA test. The TT 3972 genotype was associated with higher AUC of CPT-11 (p=0.02), APC and SN-38G (both p<0.0001, t test) compared to CT+CC patients. The frequencies of CC, CT, and TT genotypes were 0.44, 0.44, and 0.13, respectively.
CONCLUSIONS: This study identifies 3972T>C as a variant potentially affecting ABCC2 activity and suggests that ABCC2 may have a significant impact on CPT-11 clearance. These results also suggest that APC may be a substrate for ABCC2. The phenotypic effect of 3972T>C was previously unknown and further studies will test its biological function and clinical relevance. No significant financial relationships to disclose.