title: Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis B virus.
abstract: BACKGROUND
  The pharmacokinetics of a number of drugs has been shown to be impaired in patients with acute or chronic viral liver disease.
  
  
  OBJECTIVE
  To examine the effect of the asymptomatic hepatitis B virus carrier state on the metabolism of dipyrone (INN, metamizole) as a model drug.
  
  
  METHODS
  The pharmacokinetics of the metabolites of dipyrone-4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine-after a 1.0 gm oral dose of dipyrone were evaluated in nine asymptomatic carriers of hepatitis B virus with normal liver function tests and nine healthy subjects. All subjects displayed the slow acetylator phenotype.
  
  
  RESULTS
  The nonrenal (metabolic) clearance of 4-methylaminoantipyrine was significantly reduced (mean +/- SEM) (123.3 +/- 15.8 versus 182.9 +/- 15.1 ml.min-1, respectively; p < 0.02) in the carriers of hepatitis B virus compared with the healthy subjects, and the elimination half-life of this metabolite was significantly longer (3.69 +/- 0.35 versus 2.64 +/- 0.28 hours, respectively; p < 0.03). The formation clearances of 4-aminoantipyrine and 4-formylaminoantipyrine were significantly smaller in the carriers of hepatitis B virus compared with healthy subjects (33.8 +/- 6.2 versus 55.2 +/- 6.4 ml.min-1; p < 0.03, and 16.7 +/- 2.2 versus 34.2 +/- 4.2 ml.min-1; p < 0.002; respectively). However, the elimination half-life of 4-formylaminoantipyrine was found to be slightly shorter in the carriers of hepatitis B virus. No significant differences were noted between the groups in the pharmacokinetics of 4-acetylaminoantipyrine.
  
  
  CONCLUSIONS
  The metabolism of dipyrone is impaired in asymptomatic carriers of hepatitis B virus. Clinically latent infection with hepatitis B virus seems to exert a differential effect on metabolism of the drug. Oxidative pathways to produce 4-aminoantipyrine and 4-formylaminoantipyrine were significantly affected, whereas acetylation remained intact. This study provided an additional example of the effect of a virus on the disposition of a drug.
authors.affiliation: Clinical-Pharmacological Unit, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Levy
authors.forename: I
authors.initials: I
authors.lastname: Leibowich
authors.forename: E
authors.initials: E
authors.lastname: Zylber-Katz
authors.forename: Y
authors.initials: Y
authors.lastname: Ilan
authors.forename: L
authors.initials: L
authors.lastname: Granit
authors.forename: S
authors.initials: S
authors.lastname: Sviri
authors.forename: Y
authors.initials: Y
authors.lastname: Caraco
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002353:Carrier State / Q000097:blood*; D004177:Dipyrone / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006515:Hepatitis B virus; D006801:Humans; D008297:Male
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004177:Dipyrone