UCSF

In this dissertation, the two main mechanisms of adverse event occurrence namely drug-gene and drug-drug interaction were studied to identify the cause of CER induced rhabdomyolysis. Genetic variation in drug metabolizing enzymes and membrane transporters as well as other drugs can modulate the beneficial, as well as the deleterious, effects of drugs. In a study of 126 patients who developed rhabdomyolysis while taking the HMG-CoA reductase inhibitor, cerivastatin, we sought to identify genetic variants and drug-drug interactions that might explain the high incidence of rhabdomyolysis. We re-sequenced three transporter genes, ABCC2 (coding for MRP2), ABCG2 (coding for BCRP) and SLCO1B1 (coding for OATP1B1), three metabolizing enzyme genes CYP2C8, UGT1A1 and UGT1A3 and HMGCR involved in transport, metabolism and target of cerivastatin, respectively. A total of 203 SNPs were identified in these samples and of these 52 were in the coding region.

In a previously published case-control analysis of polymorphisms identified in our CYP2C8, SLCO1B1, UGT1A1 and UGT1A3 genes, the V174A SNP was found to be significantly associated with CER induced rhabdomyolysis with an odds ratio of 1.89 (95% CI,1.40-2.56). We were able to only complete in in vitro functional analysis of variants in SLCO1B1 gene on the uptake of cerivastatin in HEK293/frt cells stabely expressing SLCO1B1 reference, polymorphisms and haplotypes. The V174A SNP, along with R57Q, P155T, FS and OATP1B1*15 and N1 haplotypes were shown in in vitro assays to be associated with significant reduction (P>0.001) in CER uptake (32%, 17.9%, 72%, 3.4%, 2.1% and 5.7% of reference, respectively) compared to reference. Furthermore, clopidogrel and rofecoxib, previously identified in our cases to be associated with cerivastatin induced rhabdomyolysis at odds ratio of 29.6 (95% CI, 6.1-143) and 4.9 (95% CI, 1.1-20.8), were shown in vitro to have a significant OATP1B1 mediated interaction, inhibiting cerivastatin uptake with IC50 values of 0.32 µM (95% CI, 0.06-1.71) and 0.73 µM (95% CI, 0.3-1.8), respectively. The calculated R value for clopidogrel and rofecoxib were greater than 2, supporting a further clinical evaluation of this drug interaction.