title: Effect of rifampin and tobacco smoking on the pharmacokinetics of ropivacaine.
abstract: OBJECTIVE
  Our objective was to assess the effect of rifampin (INN, rifampicin) and tobacco smoking on the pharmacokinetics of ropivacaine.
  
  
  METHODS
  A randomized, 2-phase, crossover study was performed in both a group of 10 healthy nonsmokers and a group of 8 healthy smokers. In both groups each subject ingested daily for 5 days either placebo or 600 mg rifampin. On day 6 each subject received intravenously over 30 minutes a single dose of 0.6 mg/kg ropivacaine. Ropivacaine, 3-hydroxyropivacaine (3-OH-ropivacaine), and (S) -2',6'-pipecoloxylidide (PPX) in venous plasma and urine were measured for up to 12 hours and 24 hours, respectively. Pharmacokinetic parameters were calculated with noncompartmental methods, and t tests were used for comparisons between the phases and between the smokers and nonsmokers. The electrocardiogram was monitored for 3 hours.
  
  
  RESULTS
  There were no statistically significant differences in the area under the plasma concentration-time curve (AUC), plasma clearance (CL), or half-life (t(1/2)) of ropivacaine between the smokers and nonsmokers. However, smokers excreted in urine 31% more 3-OH-ropivacaine and 62% less PPX than nonsmokers did. Rifampin decreased the AUC of ropivacaine in nonsmokers by 52% and in smokers by 38%. In nonsmokers rifampin increased the CL of ropivacaine by 93% and shortened its t(1/2) by 25%. In smokers rifampin increased the CL of ropivacaine by 47% and shortened its t(1/2) by 20%. Rifampin decreased the urinary excretion of 3-OH-ropivacaine in nonsmokers by 74% and in smokers by 68%, and it increased the excretion of PPX by 97% and 158%, respectively. No clinically significant differences in the QTc times were found between the groups or treatments.
  
  
  CONCLUSIONS
  Tobacco smoking increases the excretion of 3-OH-ropivacaine in urine, probably because of the increased cytochrome P450 (CYP) 1A2-mediated metabolism of ropivacaine, and decreases the excretion of CYP3A4-formed PPX in urine. Rifampin considerably increases the metabolism of ropivacaine to PPX and decreases the metabolism to 3-OH-ropivacaine in both nonsmokers and smokers.
authors.affiliation: Department of Anesthesia and Intensive Care, University of Helsinki Central Hospital, PO Box 340, FIN-00029 HUS, Finland. Mika.Jokinen@hus.fi
authors.forename: M J
authors.initials: MJ
authors.lastname: Jokinen
authors.forename: K T
authors.initials: KT
authors.lastname: Olkkola
authors.forename: J
authors.initials: J
authors.lastname: Ahonen
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000328:Adult; D000577:Amides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000779:Anesthetics, Local / Q000493:pharmacokinetics*; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D019540:Area Under Curve; D004347:Drug Interactions; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D012293:Rifampin / Q000494:pharmacology*; D000077212:Ropivacaine; D012907:Smoking
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D000904:Antibiotics, Antitubercular; D000077212:Ropivacaine; D012293:Rifampin