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Pharmacokinetic Profile of Zafirlukast

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Abstract

Zafirlukast is a cysteinyl leukotriene type 1 receptor antagonist that causes bronchodilation and has anti-inflammatory properties. Clinical efficacy has been demonstrated when using oral doses of 20 to 40mg twice daily.

The pharmacokinetics of zafirlukast are best described by a two-compartment model. Maximum plasma concentrations (Cmax) were achieved 3 hours after a single oral dose of 20 or 40mg to healthy volunteers. The absolute bioavailability of zafirlukast is unknown. However, coadministration of zafirlukast with food reduces bioavailability by approximately 40%. The drug binds to plasma proteins (>99%), predominantly to albumin, and has a mean terminal elimination half-life of approximately 10 hours in both healthy volunteers and patients with asthma.

Zafirlukast undergoes extensive hepatic metabolism. Hydroxylation by cytochrome P450 (CYP) 2C9 is the major biotransformation pathway. The metabolites of zafirlukast contribute little to its overall activity. Zafirlukast is mainly eliminated in the faeces, while urinary excretion accounts for <10% of an orally administered dose.

Because of its primarily hepatic metabolism, the clearance of zafirlukast is reduced in patients with hepatic impairment. In patients with stable alcoholic cirrhosis, Cmax and area under the plasma concentration-time curve for zafirlukast were increased by 50 to 60% compared with healthy volunteers. Asymptomatic elevations of serum liver enzymes have been reported with high dosages of zafirlukast (80mg twice daily), returning to normal after cessation of the drug.

Inhibition of the CYP2C9 and CYP3A isoenzymes by zafirlukast has been reported in vitro. Zafirlukast interacts with warfarin and produces a clinically significant increase in the prothrombin time, but it does not alter the pharmacokinetics of terfenadine carboxylate, the active metabolite of terfenadine. Plasma concentrations of zafirlukast decreased when the drug was administered concomitantly with erythromycin, terfenadine or theophylline, and increased when it was coadministered with aspirin (acetylsalicylic acid). Theophylline metabolism is unchanged in most cases by zafirlukast, but there is a report of one patient with increased theophylline plasma concentrations when zafirlukast was coadministered.

Recently, cases of Churg-Strauss syndrome have been described in patients with asthma receiving zafirlukast treatment. This occurrence in patients being withdrawn from corticosteroid therapy while receiving zafirlukast has been attributed to a previously undiagnosed presence of this syndrome in these patients.

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Acknowledgements

The authors did not receive any funding in the preparation of this manuscript. There are no conflicts of interest directly relevant to the contents of this manuscript.

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  1. Department of Pulmonary Diseases, University Medical Centre Nijmegen, PO Box 9101, Nijmegen, 6500 HB, The Netherlands

    P. N. Richard Dekhuijzen

  2. Department of General Internal Medicine, University Medical Centre Nijmegen, The Netherlands

    Peter P. Koopmans

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Correspondence to P. N. Richard Dekhuijzen.

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Dekhuijzen, P.N.R., Koopmans, P.P. Pharmacokinetic Profile of Zafirlukast. Clin Pharmacokinet 41, 105–114 (2002). https://doi.org/10.2165/00003088-200241020-00003

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