Dale Whittington

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BACKGROUND Metabolism and clearance of racemic methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. Initial in vitro studies attributed methadone metabolism to cytochrome P4503A4 (CYP3A4). CYP3A4 was also assumed responsible for methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary(More)
BACKGROUND The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4.(More)
Drug-drug interactions (DDIs) with the HIV protease inhibitors (PIs) are complex, paradoxical (e.g., ritonavir/alprazolam), and involve multiple mechanisms. As part of a larger study to better understand these DDIs and to devise a framework for in vitro to in vivo prediction of these DDIs, we determined the inductive effect of ∼2 weeks of administration of(More)
BACKGROUND Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on(More)
Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage(More)
Methadone is administered as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective, with considerable unexplained variability in clearance and plasma R/S ratios. N-Demethylation of methadone in vitro is predominantly mediated by cytochrome P450 CYP3A4 and CYP2B6 and somewhat by CYP2C19. This investigation(More)
As part of a larger clinical drug-drug interaction (DDI) study aimed at in vitro to in vivo prediction of HIV protease inhibitor metabolic and transporter-based DDIs, we measured the inductive (staggered administration) and inductive plus inhibitory (simultaneously administered) effect of multiple dose ritonavir (RTV), nelfinavir (NFV), or rifampin (RIF) on(More)
We previously reported that both the concentrative (hCNT) and equilibrative (hENT) nucleoside transporters are expressed in the human liver (21). Here we report a study that investigated the expression of these transporters (transcripts and proteins) and their role in the hepatobiliary transport of nucleosides/nucleoside drugs using sandwich-cultured human(More)
BACKGROUND Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5(More)
INTRODUCTION There is considerable and unexplained individual variability in the morphine dose-effect relationship. The efflux pump P-glycoprotein regulates brain access and intestinal absorption of numerous drugs. Morphine is a P-glycoprotein substrate in vitro, and P-glycoprotein affects morphine brain access and pharmacodynamics in animals. However, the(More)