title: The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine.
abstract: 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.
authors: Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA. yasudas@georgetown.edu
authors: Sally Usdin
authors: SU
authors: Yasuda
authors: Peter
authors: P
authors: Zannikos
authors: Andrea E
authors: AE
authors: Young
authors: Karen M
authors: KM
authors: Fried
authors: Irving W
authors: IW
authors: Wainer
authors: Raymond L
authors: RL
authors: Woosley
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D002744:Chlorpheniramine; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine