The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine.
OBJECTIVE
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.
Yasuda
Sally Usdin
SU
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA. yasudas@georgetown.edu
Zannikos
Peter
P
Young
Andrea E
AE
Fried
Karen M
KM
Wainer
Irving W
IW
Woosley
Raymond L
RL
D000328:Adult; D000818:Animals; D002744:Chlorpheniramine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011802:Quinidine / Q000494:pharmacology; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000378:metabolism; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D002744:Chlorpheniramine; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine