ABSTRACT:Because rat organic cation transporter 1 (Oct1, SLC22a1) is expressed mainly in the liver and mediates drug transport, its activity may determine the hepatic handling of cationic drugs. Here, we studied the regulation mechanism of the expression of Oct1, focusing on the nuclear receptors. In vitro studies using cultured hepatocytes indicated that expression of Oct1 was up-regulated by treatment with pregnenolone-16␣-carbonitrile (PCN) and by overexpression of rat pregnane X receptor (PXR). In addition, isolated rat hepatocytes exhibited an increase of 1-methyl-4-phenylpyridinium (MPP ؉ ) uptake on treatment with PCN. When rats were subcutaneously administered PCN, an increase of biliary excretion clearance and distribution volume was observed for drugs such as MPP ؉ , metformin, and tetraethylammonium, although the effects on pharmacokinetic parameters were variable among the tested drugs. In addition, the expression of Oct2 in kidney was increased by treatment with PCN. Thus, PXR ligands appear to regulate the expression of organic cation transporters in rats and thereby to influence the pharmacokinetic properties of cationic drugs. Because PXR ligands include various clinically used drugs, alterations of hepatic drug handling may arise from interactions between cationic drugs that are substrates of Oct1 and ligands of PXR.

Sp1, a transcription factor, was required for constitutive expression of OATP2B1 in liver and small intestine, whereas HNF1alpha, which is involved in the expression of liver-specific OATPs, did not seem to play a role in OATP2B1 expression. Accordingly, it was suggested that the tissue expression profile of OATP2B1 was different from that of other liver-specific OATPs.

Cysteinyl leukotrienes (cysLTs) are 5-lipoxygenase pathway products of arachidonate that induce bronchoconstriction, vascular hyperpermeability, mucosal edema accumulation, and mucus secretion. [1][2][3] Pranlukast is a selective cysLTs receptor antagonist, and a 225 mg twice-daily dose has been used to treat bronchial asthma and allergic rhinitis in Japan.The absorption fraction of pranlukast in human is approximately 20%, based on the excretion ratio of the unchanged form in the feces following oral administration (the absolute bioavailability has not been reported). The terminal elimination half-life of pranlukast in plasma is approximately 2 h. Pranlukast is minimally excreted in the urine. The major metabolic pathway of pranlukast is shown in Fig. 1. The plasma-binding of pranlukast is more than 99%, and the major binding protein is albumin.To date, it has been very difficult to predict drug-drug interactions with pranlukast in the clinical setting due to a lack of information. Therefore, we conducted in vitro experiments using human liver microsomes to allow us to evaluate the potential for drug-drug interactions, based on the metabolism and the inhibitory effects of pranlukast. MATERIALS AND METHODS MaterialsPranlukast and 6-methyl-4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran (ONO-RS-425, an internal standard for pranlukast), were synthesized at Ono Pharmaceutical Co., Ltd. (Osaka, Japan). a-Naphthoflavone, quinideine, 4-hydroxybenzoic acid n-butyl ester and 4-hydroxybenzoic acid n-amyl ester were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Tranylcypromine, terfenadine, metoprolol, tolbutamide, erythromycin and roxithromycin were pur- We investigated the metabolism of pranlukast, a selective leukotriene agonist, and the potential for drugdrug interactions. Although cytochrome P450 (CYP) 3A4 appeared to be the major cytochrome P450 isoform involved in the metabolism of pranlukast, the results suggested that pranlukast metabolism was inhibited less than 50% by ketoconazole, a reversible CYP3A4 inhibitor, or by anti-CYP3A4 antibodies. Irreversible macrolide CYP3A4 inhibitors, clarithromycin, erythromycin and roxithromycin, exhibited little effect on pranlukast metabolism. On the other hand, pranlukast reversibly inhibited CYP2C8 and/or 2C9, and CYP3A4, with K i values of 3.9 and 4.1 m mmol/l, respectively. The [I] in,max,u /K i ratios were 0.004 and 0.003, respectively. The K i values were about 300-fold greater than the [I] in,max,u , therefore it is suggested that, at clinical doses, pranlukast will not affect the pharmacokinetics of concomitantly administered drugs that are primarily metabolized by CYP2C8 and/or 2C9 or CYP3A4.

TCI of landiolol hydrochloride is useful for controlling HR, and the PK parameters of landiolol in gynecologic patients were similar to those in healthy male volunteers and best described by a 2-compartment model with lag time.

We examined the efficacy, safety, and tolerability of ONO‐4474 in Japanese patients with osteoarthritis (OA) of the knee. In this multicenter, placebo‐controlled, randomized, double‐blind, parallel‐group comparative study, patients with moderate to severe OA who were refractory to nonsteroidal anti‐inflammatory drugs were orally administered 100 mg of ONO‐4474 twice daily for 28 days. The primary end point was knee pain during walking, assessed by visual analog scale over 24 hours (VAS24). Treatment‐emergent adverse events (TEAEs) and adverse drug reactions were reported for safety. In total, 110 patients were randomized (1:1) to receive placebo or ONO‐4474. The mean (standard deviation) change in VAS24 scores at week 4 was −26.9 (25.0) mm in the ONO‐4474 group and −19.5 (19.6) mm in the placebo group. The difference (ONO‐4474 group − placebo group) in posterior mean change in VAS24 at week 4 was −5.8 (posterior standard deviation, 4.4; 95% confidence interval, −14.3 to 2.8) mm. TEAEs were reported in 41.8% of patients in the ONO‐4474 group and 18.2% of patients in the placebo group. The most common TEAEs in the ONO‐4474 group related to the musculoskeletal system and the peripheral and central nervous systems were myalgia (7.3%), arthralgia (5.5%), dizziness (3.6%), and hypoesthesia (3.6%). Four patients from the ONO‐4474 group and 1 patient from the placebo group discontinued treatment because of AEs; however, none were judged to be serious, and all patients recovered or were recovering after discontinuation. ONO‐4474 is a novel tropomyosin receptor kinase inhibitor that has an analgesic effect in patients with OA.