Showing papers by "Richard B. Kim published in 2011"
TL;DR: The clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism is demonstrated.
85 citations
TL;DR: OATP1B3 polymorphisms that result in altered expression, substrate specificity, and pH-dependent activity may be of potential relevance to hepatic clearance of substrate drugs in vivo.
Abstract: Objective
The uptake carrier Organic Anion-transporting Polypeptide 1B3 (OATP1B3, gene SLCO1B3) is involved in the hepatic clearance of xenobiotics including statins, taxanes and mycophenolic acid. We thought to assess the SLCO1B3 coding region for yet unidentified polymorphisms, and to analyze their functional relevance.
80 citations
TL;DR: Indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism, and to demonstrate the utility of the global PK-PD model, it is compared with previously established warFarin dosing algorithms.
Abstract: Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (Imax) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for Imax were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy.
74 citations
TL;DR: Variation in expression and function of this transporter may alter central nervous system entry and the attained intracellular concentration in such breast cancer cells and therefore may prove to be of relevance to therapeutic outcome.
Abstract: Tamoxifen is widely prescribed to patients with estrogen receptor-positive breast cancer, and it is a prodrug that requires bioactivation by cytochrome P450 enzymes CYP2D6 and 3A4 to generate the active metabolite, endoxifen Large interpatient variability in endoxifen plasma levels has been reported, and polymorphisms in CYP2D6 have been implicated as a major determinant of such variability However, little is known regarding the role of drug transporters such as P-glycoprotein [multidrug resistance 1 (MDR1), ATP-binding cassette B1 (ABCB1)] to endoxifen disposition and response Therefore, we determined the ability of P-glycoprotein to transport endoxifen in vitro, using a polarized human P-glycoprotein-overexpressing cell line Markedly higher transport of endoxifen was observed in the basal-to-apical direction, which was abrogated in the presence of the potent and specific P-glycoprotein inhibitor (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979) To validate the in vivo relevance of P-glycoprotein to endoxifen disposition, plasma and tissue concentrations were also determined in Mdr1a-deficient mice after oral administration of endoxifen Plasma endoxifen levels did not significantly differ between wild-type and Mdr1a-deficient mice However, brain concentrations of endoxifen were nearly 20-fold higher in Mdr1a-deficient mice compared to wild-type mice Because P-glycoprotein is highly expressed at the blood-brain barrier and in some breast cancer tumors, variation in expression and function of this transporter may alter central nervous system entry and the attained intracellular concentration in such breast cancer cells and therefore may prove to be of relevance to therapeutic outcome
66 citations
TL;DR: In a study in patients with cancer, imatinib absorption was not associated with OATP1A2 variants and was unaffected by rosuvastatin, and these findings highlight the importance of verifying in a clinical setting the drug–transporter interactions observed in in vitro tests.
Abstract: The bioavailability of orally administered imatinib is >90%, although the drug is monocationic under the acidic conditions in the duodenum. In vitro, we found that imatinib is transported by the intestinal uptake carrier organic anion transporting polypeptide (OATP1A2) and that this process is sensitive to pH, rosuvastatin, and genetic variants. However, in a study in patients with cancer, imatinib absorption was not associated with OATP1A2 variants and was unaffected by rosuvastatin. These findings highlight the importance of verifying in a clinical setting the drug-transporter interactions observed in in vitro tests.
56 citations
TL;DR: SNPs located in MRP2 nucleotide-binding domains (NBDs) demonstrated significantly decreased ATPase activity and only modestly decreased affinity for ATP compared with WT, and SNPs in the NBDs variably decreased the transport of all substrates.
Abstract: BackgroundMultidrug resistance-associated protein 2 (MRP2; ABCC2) mediates the biliary excretion of glutathione, glucuronide, and sulfate conjugates of endobiotics and xenobiotics. Single nucleotide polymorphisms (SNPs) of MRP2 contribute to interindividual variability in drug disposition and ultima
31 citations
TL;DR: The findings reveal that OATP1B‐mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis.
28 citations
TL;DR: This study systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity.
Abstract: Background and Aims
The major transporter responsible for bile acid uptake from the intestinal lumen is the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). Analysis of the SLC10A2 gene has identified a variety of sequence variants including coding region single nucleotide polymorphisms (SNPs) that may influence bile acid homeostasis/intestinal function. In this study, we systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity.
27 citations
TL;DR: Mouse models of solute carrier function are providing important new insights into the in vivo relevance of these proteins and their contribution to drug disposition and response.
Abstract: Solute carriers represent a superfamily of membrane-bound proteins that are capable of transporting endogenous hormones as well as structurally divergent xenobiotics, including many drugs in clinical use. Solute carriers facilitate drug access to specific tissues or organs, and therefore their inhibition may result in unintended transport-mediated drug interactions or loss of therapeutic efficacy. Mouse models of solute carrier function are providing important new insights into the in vivo relevance of these proteins and their contribution to drug disposition and response.
Clinical Pharmacology & Therapeutics (2011) 89 4, 612–616. doi:10.1038/clpt.2011.2
17 citations
1 citations
TL;DR: A retrospective, cohort study of consecutive patients enrolled in an academic OAT clinic between September 2008 and February 2011 evaluated the performance of 4 validated BRS for predicting MB and CRNMB, finding the best predictive ability for both MB and MB + CRN MB was for CBRM and HEMORR2HAGES.