No abstract

Publicly available genetic and expression data on lymphoblastoid cell lines (LCLs) make them a unique resource for understanding the genetic underpinnings of pharmacological outcomes and disease. LCLs have been used for pharmacogenomic discovery and validation of clinical findings associated with drug response. However, variation in cellular growth rate, baseline Epstein-Barr virus (EBV) copy number and ATP levels can all be confounders in such studies. Our objective is to better define confounding variables that affect pharmacological end points in LCLs. To this end, we evaluated the effect of these three variables on drug-induced cytotoxicity in LCLs. The drugs evaluated included daunorubicin, etoposide, carboplatin, cisplatin, cytarabine, pemetrexed, 5 0 -deoxyfluorouridine, vorinostat, methotrexate, 6-mercaptopurine, and 5-fluorouracil. Baseline ATP or EBV copy number were not significantly correlated with cellular growth rate or druginduced cytotoxicity. In contrast, cellular growth rate and drug-induced cytotoxicity were significantly, directly related for all drugs except vorinostat. Importantly, cellular growth rate is under appreciable genetic influence (h 2 ¼ 0.30-0.39) with five suggestive linkage regions across the genome. Not surprisingly, a percentage of SNPs that significantly associate with druginduced cytotoxicity also associate with cellular growth rate (Pp0.0001). Studies using LCLs for pharmacologic outcomes should therefore consider that a portion of the genetic variation explaining drug-induced cytotoxicity is mediated via heritable effects on growth rate.

Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The influence of potential covariates was evaluated. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The data were well described by a two-compartment model incorporating a saturable Michaelis–Menten kinetic absorption process. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption.

Experimental evidence suggests HNF1alpha regulates UGT expression. This study investigates (1) whether the variability in HNF1alpha expression is associated with the variability in UGT1A1, UGT1A9 and UGT2B7 expression in human livers and (2) the functionality of 12 HNF1alpha variants using mRNA expression as phenotype. Controlling for known UGT variation in cis-acting elements known to affect UGT expression, we demonstrate that a combination of HNF1alpha mRNA levels and UGT genotype predicts variance in UGT expression to a higher extent than UGT genotype alone. None of the HNF1alpha polymorphisms studied, however, seem to have an effect on HNF1alpha, UGT1A1, UGT1A9 and UGT2B7 expression, ruling out their functional role. Our data provide evidence for HNF1alpha being a determinant of UGT1A1, UGT1A9 and UGT2B7 mRNA expression. However, the amount of UGT intergenotype variability explained by HNF1alpha expression appears to be modest, and further studies should investigate the role of multiple transcription factors.