Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the hepatic clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, hepatic uptake clearance rather than metabolic intrinsic clearance is the more important determinant of hepatic clearances. The importance of the unbound concentration ratio (liver/blood), K p,uu , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC 50 of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.

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It is well known that transporter proteins play a key role in governing drug absorption, distribution, and elimination in the body, and, accordingly, they are now considered as causes of drug-drug interactions and interindividual differences in pharmacokinetic profiles. Polarized tissues directly involved in drug disposition (intestine, kidney, and liver) and restricted distribution to naive sanctuaries (blood-tissue barriers) asymmetrically express a variety of drug transporters on the apical and basolateral sides, resulting in vectorial drug transport. For example, the organic anion transporting polypeptide (OATP) family on the sinusoidal (basolateral) membrane and multidrug resistance-associated protein 2 (MRP2/ABCC2) on the apical bile canalicular membrane of hepatocytes take up and excrete organic anionic compounds from blood to bile. Such vectorial transcellular transport is fundamentally attributable to the asymmetrical distribution of transporter molecules in polarized cells. Besides the apical/basolateral sorting direction, distribution of the transporter protein between the membrane surface (active site) and the intracellular fraction (inactive site) is of practical importance for the quantitative evaluation of drug transport processes. The most characterized drug transporter associated with this issue is MRP2 on the hepatocyte canalicular (apical) membrane, and it is linked to a genetic disease. Dubin-Johnson syndrome is sometimes caused by impaired canalicular surface expression of MRP2 by a single amino acid substitution. Moreover, single nucleotide polymorphisms in OATP-C/SLC21A6 (SLCO1B1) also affect membrane surface expression, and actually lead to the altered pharmacokinetic profile of pravastatin in healthy subjects. In this review article, the asymmetrical transporter distribution and altered surface expression in polarized tissues are discussed.

Hepatotoxicity of diclofenac has been known in experimental animals and humans but its mechanism has not been fully understood. The present study examined the role of mitochondrial permeability transition (MPT) in the pathogenesis of diclofenac-induced hepatocyte injury by using isolated mitochondria and primary culture hepatocytes from rats. Incubation of energized mitochondria with succinate in the presence of Ca 2؉ and diclofenac resulted in mitochondrial swelling, leakage of accumulated Ca 2؉ , membrane depolarization, and oxidation of nicotinamide adenine dinucleotide phosphate and protein thiol. All of these phenomena were suppressed by coincubation of the mitochondria with cyclosporin A, a typical inhibitor of MPT, showing that diclofenac opened the MPT pore. It was also suggested that reactive oxygen species probably generated during mitochondrial respiration and/or voltage-dependent mechanism was involved in MPT, which are proposed as mecha D iclofenac is a nonsteroidal anti-inflammatory drug (NSAID) widely used clinically. Hepatotoxicity is one of the side effects associated with the drug. Various mechanisms for the diclofenac-induced liver injury were proposed, but have not been fully understood. The diclofenac liver toxicity in humans is idiosyncratic, 1 and immunologic and metabolic idiosyncrasies have been suggested. 2,3 Thus, metabolic activation of this drug has been a focus, 4-6 and several reactive metabolites were proposed as candidates to contribute to the toxicity in experimental animals and humans. [7][8][9][10] On the other hand, we currently obtained the following evidence that diclofenac rather than its metabolite was responsible for the toxicity. Diclofenac toxicity to rat hepatocytes was not prevented by inhibiting its oxidation of conjugative metabolism. 11 NSAIDs including diclofenac that have a common chemical structure have hepatocyte toxicity, and these toxic NSAIDs depleted cellular adenosine triphosphate (ATP) before the enzyme leakage. 11 The toxic NSAIDs have been shown to be uncouplers of mitochondrial oxidative phosphorylation, which results in impairment of ATP synthesis. 12 Furthermore, rescue of hepatocytes from depletion of ATP conferred protection against hepatocyte injury induced by diclofenac. 13 It was thus concluded that the uncoupling property of diclofenac plays a crucial role in its hepatotoxicity, whereas an additional and/or alternative step is necessary to explain the mechanism for clinically observed idiosyncratic liver injury.Mitochondrial permeability transition (MPT) is recently focused as a mechanism for drug-induced hepatocyte necrosis and apoptosis. [14][15][16] The MPT represents an abrupt increase in permeability of the mitochondrial inner membrane to allow solutes with a molecular weight less than 1,500. 17 The MPT is promoted by the accumulation of excessive Ca 2ϩ and stimulated by various compounds and conditions. It leads to dissipation of membrane potential (⌬⌿), uncoupling, loss of preaccumulated Ca 2ϩ , and expansion of the matrix volume. Uncou...