Transporter‐mediated drug–drug interactions (DDIs) are among the most important of the clinically relevant pharmacokinetic DDIs. We investigated the validity of a static prediction of area under the ...plasma concentration–time curve (AUC) ratios (AUCRs; AUCwith inhibitor/AUCcontrol) using in vitro inhibition profiles, and selected the types of assumptions that improved the prediction accuracy with minimizing false‐negative predictions. We used data from 58 DDI studies involving 12 substrates of hepatic organic anion–transporting polypeptides (OATPs). With original assumptions regarding the maximal increase in intestinal availability, maximum unbound concentration at the inlet to the liver, and inhibition of only the hepatic uptake process, the predicted AUCRs were comparable to those reported within a two/threefold error margin in 44/52 studies, whereas in 16 studies, the predictions were judged to be false‐negatives. When the inhibitory effects on both hepatic uptake and efflux/metabolisms were considered, the overall prediction accuracy became worse, although the false‐negative prediction decreased to 11 studies. This illustrates that if appropriate assumptions are selected, unnecessary clinical DDI studies can be reasonably avoided.
Clinical Pharmacology & Therapeutics (2012); 91 6, 1053–1064. doi:10.1038/clpt.2011.351
Clearance of atorvastatin occurs through hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative ...importance of OATPs and CYP3A4 in the hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe substrates for OATPs (pravastatin) and CYP3A4 (midazolam) was orally administered to eight healthy volunteers. The pharmacokinetics of this cocktail was observed at baseline, after an oral dose of 600 mg rifampicin (an inhibitor of OATPs), and after an intravenous dose of 200 mg itraconazole (a CYP3A4 inhibitor). Rifampicin increased the pravastatin dose‐normalized area under the plasma concentration–time curve (AUC) (4.6‐fold), and itraconazole significantly increased the midazolam dose‐normalized AUC (1.7‐fold). The atorvastatin dose‐normalized AUC increased 12‐fold when coadministered with rifampicin but did not change when coadministered with itraconazole. These results indicate that hepatic uptake via OATPs makes the dominant contribution to the hepatic elimination of atorvastatin at a subtherapeutic microdose.
Clinical Pharmacology & Therapeutics (2011) 90 4, 575–581. doi:10.1038/clpt.2011.142
This Commentary focuses on genetic polymorphisms in membrane transporters. We present two polymorphisms for which there is a compelling body of literature supporting their clinical relevance: OATP1B1 ...(c.521T>C, p.V174A, rs4149056) and BCRP (c.421C>A, p.Q141K, rs2231142). The clinical evidence demonstrating their role in variation in pharmacokinetics and pharmacodynamics is described along with their allele frequencies in ethnic populations. Recommendations for incorporating studies of transporter polymorphisms in drug development are provided, along with the regulatory implications.
Clinical Pharmacology & Therapeutics (2013); 94 1, 23–26. doi:10.1038/clpt.2013.12
Various endogenous probes have been identified for a number of hepatic and renal drug transporters and available clinical data indicate that they could be leveraged in phase I trials to facilitate ...subject phenotyping and drug–drug interaction (DDI) assessment. Despite the progress, however, it is recognized that the menu of probes needs expanding, that existing probes need further characterization and validation, and that compound files need to be built in support of probe absorption‐metabolism‐distribution‐excretion‐DDI modeling exercises.
A microdose study of metformin was conducted to investigate the predictability of drug–drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 µg) or ThD (250 mg) ...of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance of metformin by 23 and 35% at the microdose and ThD, respectively. At ThD, but not at microdose, it caused significant increases in the maximum concentration (Cmax) and area under the plasma concentration–time curve (AUC) of metformin (142 and 139% of control values, respectively). Human canalicular membrane vesicles showed pyrimethamine‐inhibitable metformin uptake. Pyrimethamine did not affect plasma lactate/pyruvate after ThD of metformin but significantly reduced the renal clearance of creatinine, thereby causing elevation of plasma creatinine level. This microdose study quantitatively predicted a drug–drug interaction involving the renal clearance of metformin at ThD by pyrimethamine. Pyrimethamine is a useful in vivo inhibitor of MATE proteins.
Clinical Pharmacology & Therapeutics (2011) 89 6, 837–844. doi:10.1038/clpt.2011.36
Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, ...including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.
Clinical Pharmacology & Therapeutics (2013); 94 1, 126–141. doi:10.1038/clpt.2013.78
Because the plasma exposure levels of rosuvastatin in Asians are generally twice those in Caucasians, the starting dose for Asians in the United States is set to half of that for non‐Asians. However, ...the precise role of ethnicity in the clearance of rosuvastatin has not yet been clarified. This review focuses on ethnic variability in the clinical pharmacokinetics of 3‐hydroxy‐3‐methylglutaryl co‐enzyme A (HMG‐CoA) reductase inhibitors (statins) and angiotensin II receptor antagonists. The mechanisms of such variability are discussed quantitatively, with building a hypothetical model for pravastatin, and validated against other statins. Our analyses suggest that the ethnic variability in the plasma exposure of statins cannot be explained only by the difference in the allele frequencies of organic anion–transporting polypeptide (OATP)1B1 and breast cancer resistance protein (BCRP), and the intrinsic ethnic variability in the activity of OATP1B1 (the ratio of Japanese/Caucasians is 0.584) must be considered. Further work and validation with additional data will clarify the applicability of this model to other OATP1B1 substrates.
Clinical Pharmacology & Therapeutics (2013); 94 1, 37–51. doi:10.1038/clpt.2012.221
This study proposes a structural design for developing a medium scale composite wind turbine blade made of E-glass/epoxy for a 750
kW class horizontal axis wind turbine system. The design loads were ...determined from various load cases specified at the IEC61400-1 international specification and GL regulations for the wind energy conversion system. A specific composite structure configuration, which can effectively endure various loads such as aerodynamic loads and loads due to accumulation of ice, hygro-thermal and mechanical loads, was proposed. To evaluate the proposed composite wind turbine blade, structural analysis was performed by using the finite element method. Parametric studies were carried out to determine an acceptable blade structural design, and the most dominant design parameters were confirmed. In this study, the proposed blade structure was confirmed to be safe and stable under various load conditions, including the extreme load conditions. Moreover, the blade adapted a new blade root joint with insert bolts, and its safety was verified at design loads including fatigue loads. The fatigue life of a blade that has to endure for more than 20 years was estimated by using the well-known S–N linear damage theory, the service load spectrum, and the Spera's empirical equations. With the results obtained from all the structural design and analysis, prototype composite blades were manufactured. A specific construction process including the lay-up molding method was applied to manufacturing blades. Full-scale static structural test was performed with the simulated aerodynamic loads. From the experimental results, it was found that the designed blade had structural integrity. In addition, the measured results of deflections, strains, mass, and radial center of gravity agreed well with the analytical results. The prototype blade was successfully certified by an international certification institute, GL (Germanisher Lloyd) in Germany.
Transporters play an important role in the processes of drug absorption, distribution and excretion. In this review, we have focused on the involvement of transporters in drug excretion in the liver ...and kidney. The rate of transporter-mediated uptake and efflux determines the rate of renal and hepatobiliary elimination. Transporters are thus important as a determinant of the clearance in the body. Even when drugs ultimately undergo metabolism, their elimination rate is sometimes determined by the uptake rate mediated by transporters. Transporters regulate the pharmacological and/or toxicological effect of drugs because they limit their distribution to tissues responsible for their effect and/or toxicity. For example, the liver-specific distribution of some statins via organic anion transporters helps them to produce their high pharmacological effect. On the other hand, as in the case of metformin taken up by organic cation transporter 1, drug distribution to the tissue(s) may enhance its toxicity. As transporter-mediated uptake is a determinant of the drug elimination rate, drug–drug interactions involving the process of transporter-mediated uptake can occur. In this review, we have introduced some examples and described their mechanisms.
More recently, some methods to analyze such transporter-mediated transport have been reported. The estimation of the contributions of transporters to the net clearance of a drug makes it possible to predict the net clearance from data involving drug transport in transporter-expressing cells. Double transfected cells, where both uptake and efflux transporters are expressed on the same polarized cells, are also helpful for the analysis of the rate of transporter-mediated transcellular transport.
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