Impairment of the metabolism of dipyrone in asymptomatic carriers of the hepatitis B virus.
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.
Levy
M
M
Clinical-Pharmacological Unit, Hadassah University Hospital, Jerusalem, Israel.
Leibowich
I
I
Zylber-Katz
E
E
Ilan
Y
Y
Granit
L
L
Sviri
S
S
Caraco
Y
Y
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004177:Dipyrone