The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine.

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Yasuda SU, Zannikos P, Young AE, Fried KM, Wainer IW, Woosley RL

The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine.

Br J Clin Pharmacol. 2002 May;53(5):519-25.

PubMed ID

11994058 [ View in PubMed

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Abstract

AIMS: To examine the stereoselective disposition of chlorpheniramine and to evaluate the role of CYP2D6 in chlorpheniramine pharmacokinetics in humans. METHODS: Eight healthy volunteers (six extensive metabolizers with respect to CYP2D6 and two poor metabolizers) received a single 8 mg oral dose of rac-chlorpheniramine either given alone or following administration of quinidine 50 mg every 6 h for 2 days prior to the study day and every 6 h thereafter until the end of the study. Plasma concentrations of (S)-(+)- and (R)-(-)-enantiomers of chlorpheniramine were determined using liquid chromatography/mass spectrometry. RESULTS: In extensive metabolizers, mean Cmax was greater (12.55+/-1.51 ng ml-1vs 5.38+/-0.44 ng ml-1) and CLoral was lower (0.49+/-0.08 l h-1 kg-1vs 1.07+/-0.15 l h-1 kg-1) for (S)-(+)- than for (R)-(-)-chlorpheniramine (P<0.005). For (S)-(+)-chlorpheniramine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94+/-1.51 (P<0.01), a reduction in CLoral to 0.22+/-0.03 l h-1 kg-1 (P<0.01), and a prolongation of elimination half-life from 18.0+/-2.0 h to 29.3+/-2.0 h (P<0.001). Administration of quinidine decreased CLoral for (R)-(-)-chlorpheniramine to 0.60+/-0.10 l h-1 kg-1 (P<0.005). In CYP2D6 poor metabolizers, systemic exposure was greater after chlorpheniramine alone than in extensive metabolizers, and administration of quinidine resulted in a slight increase in CLoral. CONCLUSIONS: Stereoselective elimination of chlorpheniramine occurs in humans, with the most pharmacologically active (S)-(+)-enantiomer cleared more slowly than the (R)-(-)-enantiomer. CYP2D6 plays a role in the metabolism of chlorpheniramine in humans.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Chlorpheniramine	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details
Dexchlorpheniramine	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate Inhibitor	Details
Dexchlorpheniramine maleate	Cytochrome P450 2D6	Protein	Humans	No	Substrate Inhibitor	Details