Genetic polymorphisms of human organic anion transporting polypeptides OATP-C (SLC21A6) and OATP-B (SLC21A9) in the Japanese population were analyzed. The allele frequencies of OATP-C*1a, OATP-C*1b (N130D), OATP-C*1c (R152K and D241N), and OATP-C*5 (V174A) were 35.2, 53.7, 0, and 0.7%, respectively, in 267 healthy Japanese subjects. In the OATP-C gene, we found a novel allele called OATP-C*15 possessing two single nucleotide polymorphisms (SNPs), N130D and V174A, simultaneously. The allele frequency of OATP-C*15 was 3.0%. The allele frequencies of OATP-B*1, OATP-B*2 (T392I), and OATP-B*3 (S486F) were 69.1, 0, and 30.9%, respectively. For functional analysis, each OATP-C and OATP-B allele was expressed in human embryonic kidney (HEK293) cells, and the kinetics of uptake of [ 3 H]estrone-3-sulfate was determined. In the case of OATP-C alleles, no significant alteration in K m or V max values of [ 3 H]estrone-3-sulfate uptake was observed, even when the V max values were corrected for the expression levels of OATP-C protein. In contrast, V max , corrected with the expression level of OATP-B*3, was decreased to 42.5% of OATP-B*1, whereas the K m values were comparable. Since the frequency of the OATP-B*3 allele was high (30.9%) in our subjects, the SNP of S486F may affect the physiological function and/or pharmacological effects of OATP-B substrates in vivo.

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2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) is an orally available, longacting nonprostanoid prostacyclin receptor (IP receptor) agonist prodrug. In a rat model of pulmonary hypertension induced by monocrotaline (MCT), NS-304 ameliorated vascular endothelial dysfunction, pulmonary arterial wall hypertrophy, and right ventricular hypertrophy, and it elevated right ventricular systolic pressure and improved survival. {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), the active form of NS-304, is much more selective for the IP receptor than are the prostacyclin analogs beraprost and iloprost, which also have high affinity for the EP 3 receptor. To investigate the effect of receptor selectivity on vasodilation of the pulmonary artery, we assessed the relaxant response to these IP agonists in rats. MRE-269 induced vasodilation equally in large pulmonary arteries (LPA) and small pulmonary arteries (SPA), whereas beraprost and iloprost induced less vasodilation in SPA than in LPA. An EP 3 agonist, sulprostone, induced SPA and LPA vasoconstriction, and an EP 3 antagonist attenuated the vasoconstriction. Beraprost showed EP 3 agonism and induced LPA and SPA vasoconstriction, whereas the EP 3 antagonist inhibited this vasoconstriction and enhanced beraprost-and iloprost-induced SPA vasodilation. These findings suggest that the EP 3 agonism of beraprost and iloprost interfered with the SPA vasodilation resulting from their IP receptor agonism. Endothelium removal markedly attenuated the vasodilation induced by beraprost, but not that induced by MRE-269 or iloprost. Moreover, the vasodilation induced by beraprost and iloprost, but not that induced by MRE-269, was more strongly attenuated in LPA from MCT-treated rats than from normal rats. NS-304 is a promising alternative medication for pulmonary arterial hypertension with prospects for good patient compliance.Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by a progressive increase in pulmonary arterial pressure and pulmonary vascular resistance, leading ultimately to right ventricular failure and death (Rich et al., 1987;Farber and Loscalzo, 2004). The pathogenesis of PAH includes at least three processes occurring in small pulmonary arteries (SPA): vasoconstriction, vascular remodeling, and thrombosis (Rubin, 1997;Runo and Loyd, 2003).Prostacyclin (PGI 2 ) is a potent endogenous vasodilator and inhibitor of platelet aggregation that acts at the PGI 2 receptor (IP receptor) (Namba et al., 1994). PGI 2 contributes to the maintenance of homeostasis and has various other physiological effects in many organ systems (Narumiya et al., 1999 ABBREVIATIONS: PAH, pulmonary arterial hypertension; SPA, small pulmonary arteries; PGI 2 , prostacyclin; IP receptor, PGI 2 receptor; PH, pulmonary hypertension; MCT, monocrotaline; NS-304, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide; MRE-269, {4-[(5,6-diphenylpyrazin-2-yl)(isopropy...

This article is available online at http://dmd.aspetjournals.org ABSTRACT:CYP2C8 plays important roles in metabolizing therapeutic drugs and endogenous compounds. Although genetic polymorphisms of CYP2C8 were reported, there is little information on CYP2C8 polymorphisms in the Japanese population. In the present study, we screened for previously described polymorphisms in the coding region of this gene using polymerase chain reaction (PCR)-restriction fragment length polymorphism or allele specific-PCR analyses. Eleven polymorphisms of CYP2C8*2 (I269F), CYP2C8*3 (R139K, K399R), CYP2C8*4 (I264M), CYP2C8*5 (frameshift), T130N, E154D, N193K, K249R, L390S, P404A, and H411L have been comprehensively investigated in at least 200 Japanese individuals. A single subject was heterozygous for CYP2C8*5, and the allele frequency was calculated as 0.0025. The other single nucleotide polymorphisms (SNPs) were not found in the Japanese subjects in the present study. Thus, it appears that the frequencies of these alleles in Japanese are extremely low. In addition, concerning the SNPs of T130N, E154D, N193K, K249R, and H411L, it remains clear that these alleles exist as polymorphisms or represent sequence errors or cloning artifacts. Although several SNPs such as CYP2C8*2, CYP2C8*3, CYP2C8*4, and P404A have been reported to reduce the enzymatic activity, pharmacokinetic abnormalities of drugs metabolized by polymorphic CYP2C8 might be rare in Japanese.

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