In Vitro Metabolism and Inhibitory Effects of Pranlukast in Human Liver Microsomes

Abstract

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.

Isolation, Characterization, and Toxicity Study of Stress Degradation Products of Pranlukast Hydrate

“…Furthermore, it helps establish the degradation pathway and the mechanism of formation of a DP. It also helps elucidate the intrinsic stability of the molecule. , The knowledge of the drug’s DPs can help decrease the toxicity and side effects of the drug. Hence, the complete characterization of DPs is mandatory .…”

“…One stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method has reported . Few RP-HPLC methods have reported of PRN in formulation, PRN and its metabolism in plasma, , PRN pharmacokinetics in plasma, and few LC–MS/MS (liquid chromatography–tandem mass spectrometry) methods have reported for PRN in plasma. ,, But no studies are available for the isolation and characterization of the stress DPs of this drug. Hence, the study aims to develop and validate a novel stability-indicating liquid chromatography–electrospray ionization–quadrupole time of flight tandem mass spectrometry (LC-ESI-QTOF-MS/MS) method for the determination of PRN along with isolation, in vitro and in silico toxicity study of major DPs of PRN.…”

“…8 One stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method has reported. 9 Few RP-HPLC methods have reported of PRN in formulation, 10 PRN and its metabolism in plasma, 5,11 PRN pharmacokinetics in plasma, 12 and few LC−MS/MS (liquid chromatography−tandem mass spectrometry) methods have reported for PRN in plasma. 1,2,13 But no studies are available for the isolation and characterization of the stress DPs of this drug.…”

Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances

“…6 Focusing on the metabolism of pranlukast, the studies performed so far have shown that biotransformation reactions occur on the side chains instead of the chromone core. 7 The relevance of the chromone scaffold in medicinal chemistry has been an up-and-coming area of study. Publications on chromone-based compounds have been increasingly acknowledged, a process driven by recent progress in development of chromone-based drug candidates.…”

“…They have been used since ancient times in traditional medicine and are well-known by their diversity of pharmacological properties, such as antiallergic, anti-inflammatory, antidiabetic, antitumor, and antimicrobial. , Moreover, the use of chromone-based drugs in the therapy of asthma has been extensively explored, mainly as bronchodilators. , The drug discovery processes have culminated in the development of disodium cromoglycate (DSCG) and pranlukast (Figure ), which are useful drugs for the treatment of mild to moderate asthma and allergic rhinitis, respectively . Focusing on the metabolism of pranlukast, the studies performed so far have shown that biotransformation reactions occur on the side chains instead of the chromone core …”