Pharmacokinetics And Metabolism

The leukotriene-modifying drugs are administered orally. Zafirlukast is absorbed rapidly, with >90% bioavailability. At therapeutic plasma concentrations, it is >99% protein-bound. Zafirlukast is metabolized extensively by hepatic CYP2C9. The parent drug is responsible for its therapeutic activity, with metabolites being <10% as effective. The t122 of zafirlukast is —10 hours.

Montelukast is absorbed rapidly, with ~60—70% bioavailability. At therapeutic concentrations, it is highly protein-bound (99%). It is metabolized extensively by CYP3A4 and CYP2C9. The t122 of montelukast is 3-6 hours.

Zileuton is absorbed rapidly on oral administration and is metabolized extensively by CYPs and by UDP-glucuronosyltransferases. The parent molecule is responsible for its therapeutic action. Zileuton is a short-acting drug with a t122 of ~2.5 hours and also is highly protein-bound (93%).

MECHANISM OFACTION IN ASTHMA Leukotriene-modifying drugs act either as competitive antagonists of leukotriene receptors or by inhibiting the synthesis of leukotrienes. The pharmacological properties of leukotrienes are discussed in detail in Chapter 25.

Leukotriene-Receptor Antagonists Cysteinyl leukotrienes (CysLTs) include leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4). All the CysLTs are potent constrictors of bronchial smooth muscle. On a molar basis, LTD4 is —1000 times more potent than is histamine as a bronchoconstrictor. The receptor responsible for the bronchoconstrictor effect of leukotrienes is the CysLTj receptor. Although each of the CysLTs is an agonist at the CysLTj receptor, LTE4 is less potent than either LTC4 or LTD4. Zafirlukast and montelukast are selective high-affinity competitive antagonists for the CysLTj receptor. Pranlukast is another CysLTj-receptor antagonist used in some countries in the treatment of asthma, but it is not approved for use in the U.S.

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