The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin*

Gorski, J. Christopher; Jones, David R.; Haehner‐Daniels, Barbara D.; Hamman, Mitchell A.; O’Mara, Edward; Hall, Stephen D.

doi:10.1016/s0009-9236(98)90146-1

Cited by 390 publications

(409 citation statements)

References 38 publications

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“…A reported clinical CYP3A-mediated DDI has also been reported for clarithromycin (Gorski et al, 1998). After an oral-dosing regimen of 500 mg b.i.d.…”

Section: Time-dependent Inhibition Using Plated Human Cell Systemsmentioning

confidence: 78%

Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

Albaugh

Fullenwider²,

Fisher³

et al. 2012

Drug Metab Dispos

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ABSTRACT:The current studies assessed the utility of freshly plated hepatocytes, cryopreserved plated hepatocytes, and cryopreserved plated HepaRG cells for the estimation of inactivation parameters k inact and K I for CYP3A. This was achieved using a subset of CYP3A time-dependent inhibitors (fluoxetine, verapamil, clarithromycin, troleandomycin, and mibefradil) representing a range of potencies.

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“…A reported clinical CYP3A-mediated DDI has also been reported for clarithromycin (Gorski et al, 1998). After an oral-dosing regimen of 500 mg b.i.d.…”

Section: Time-dependent Inhibition Using Plated Human Cell Systemsmentioning

confidence: 78%

Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

Albaugh

Fullenwider²,

Fisher³

et al. 2012

Drug Metab Dispos

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“…The inhibitory activities of clarithromycin and erythromycin on midazolam metabolism were greater than that of roxithromycin in this study, suggesting that the in vitro metabolism results would reflect in vivo interactions. [8][9][10][11][12] Since the inhibitory activities of all tested macrolides on pranlukast metabolism were very weak, it is considered that the in vivo effects of macrolides on pranlukast metabolism would be small.…”

Section: Discussionmentioning

confidence: 99%

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

Yoneda

Matsumoto

Sutoh

et al. 2009

Biological & Pharmaceutical Bulletin

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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.

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“…It has been confirmed that clarithromycin reduces the elimination of drugs metabolized by CYP3A, such as midazolam (Gorski et al, 1998), omeprazole (Furuta et al, 1999), and cisapride (van Haarst AD et al, 1998;Piquette, 1999) in vivo. Because olopatadine, like imipramine, contains an alkylamino moiety there was a possibility that it also might inhibit P450 activities via the formation of MIC.…”

Section: Fig 2 Mass Spectra Of M1 (A) M3 (B) and Olopatadine (C)mentioning

confidence: 92%

Effects of Olopatadine, a New Antiallergic Agent, on Human Liver Microsomal Cytochrome P450 Activities

Kajita

Inano²,

Fuse³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Olopatadine, a new histamine H 1 receptor-selective antagonist, is a tricyclic drug containing an alkylamino moiety. Some compounds containing a similar alkylamino group form a cytochrome P450 (P450) -iron (II)-nitrosoalkane metabolite complex [metabolic intermediate complex (MIC)], thereby causing quasi-irreversible inhibition of the P450. There was concern that olopatadine might also form MICs, therefore, the present investigation was undertaken to explore this possibility. We identified the enzymes catalyzing olopatadine metabolism and investigated the effect of olopatadine on human P450 activities. During incubation with human liver microsomes in the presence of a NADPH-generating system, olopatadine was metabolized to two metabolites, M1 (N-monodemethylolopatadine) and M3 (olopatadine N-oxide) at rates of 0.330 and 2.50 pmol/min/mg protein, respectively. Troleandomycin and ketoconazole, which are both selective inhibitors of CYP3A, significantly reduced M1 formation but specific inhibitors of other P450 isozymes did not decrease M1 formation. Incubation of olopatadine with cDNA-expressed human P450 isozymes confirmed that M1 formation was almost exclusively catalyzed by CYP3A4. The formation of M3 was enhanced by N-octylamine and was inhibited by thiourea. High specific activity of M3 formation was exhibited by cDNA-expressed flavin-containing monooxygenase (FMO)1 and FMO3. Olopatadine did not inhibit P450 activities when it was simultaneously incubated with substrates for different P450 isozymes. Also, P450 activities in human liver microsomes were unaffected by pretreatment with olopatadine or M1. Furthermore, spectral analysis revealed that neither olopatadine nor M1 formed an MIC. Therefore, it is unlikely that olopatadine will cause drugdrug interactions involving P450 isozymes.Olopatadine, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, is a new histamine H 1 receptorselective antagonist (Ohshima et al., 1992) that is used in the clinic for the treatment of allergic rhinitis, chronic urticaria, eczema, dermatitis, and conjunctivitis. After oral administration of [ 14 C]olopatadine to rats and dogs, the main metabolic pathways were 1) N-demethylation to M1 and M2, the N-monodemethyl and N-didemethyl analogs, respectively; 2) hydroxylation of dihydrodibenz [b,e]oxepin ring (M5); and 3) sulfoconjugation of M5 (M4) and N-oxidation (M3) (Ohishi et al., 1995; Fig. 1). After oral administration of olopatadine to human subjects, the metabolites detected in plasma were M1 and M3, but the areas under the plasma concentration-time curve of both M1 and M3 were lower than that of unchanged drug (Fujita et al., 1999). The main elimination pathway of olopatadine in human subjects and animals was via excretion of unchanged drug in urine. Urinary metabolites were mainly M1 and M3, but the amounts of these metabolites were much lower than that of unchanged drug in rat, dog (Ohishi et al., 1995), and human (Tsuno...

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The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin*

Cited by 390 publications

References 38 publications

Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

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

Effects of Olopatadine, a New Antiallergic Agent, on Human Liver Microsomal Cytochrome P450 Activities

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