title: Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel.
abstract: OBJECTIVE
  Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter-individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel.
  
  
  METHODS
  Seventy-six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non-compartmental analysis was used to determine peak plasma concentration (C(max)), time to peak plasma concentration (T(max)), elimination half-life (t(1/2e)), and area under the curve (AUC(0-->infinity)).
  
  
  RESULTS
  One-third of volunteers were smokers (n = 27) and one-half had abnormal body weight (n = 39). Smokers had lower AUC(0-->infinity) (smokers: 6.24 +/- 2.32 microg/h/mL vs. non-smokers: 8.93 +/- 3.80 microg/h/mL, P < 0.001) and shorter half-life (smokers: 5.46 +/- 2.99 vs. non-smokers: 8.43 +/- 4.26, P = 0.001). Smoking behaviour had no influence on C(max) (P = 0.3) and T(max) (P = 0.7). There was no statistically significant difference in C(max), AUC(0-->infinity), T(max) and t(1/2e) between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean +/- SE; 26.93 +/- 0.16 vs. 23.11 +/- 0.27). In general, the pharmacokinetic parameters were characterized by considerable inter-individual differences (C(max) = 3.09 +/- 0.99 microg/mL, CV = 32%), (T(max) =0.76 +/- 0.24 h, CV = 31.6%), (AUC(0-->infinity) = 7.98 +/- 3.58 microg/h/mL, CV = 44.8%), and (t(1/2e) = 7.38 +/- 4.10 h, CV = 55.6%).
  
  
  CONCLUSIONS
  Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking-cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.
authors.affiliation: Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman, Jordan. ayousef@ju.edu.jo
authors.forename: A-M
authors.initials: AM
authors.lastname: Yousef
authors.forename: T
authors.initials: T
authors.lastname: Arafat
authors.forename: N R
authors.initials: NR
authors.lastname: Bulatova
authors.forename: R
authors.initials: R
authors.lastname: Al-Zumyli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001835:Body Weight; D000077144:Clopidogrel; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D012907:Smoking / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D010975:Platelet Aggregation Inhibitors; C528640:clopidogrel carboxylic acid; D000077144:Clopidogrel; D013988:Ticlopidine