Dipyrone metabolism in liver disease.
OBJECTIVE
Dipyrone is an analgesic, antipyretic, and anti-inflammatory drug. After oral administration it is hydrolyzed to 4-methylaminoantipyrine and further metabolized to 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine. This study investigated the disposition of dipyrone metabolites in 12 hospitalized patients with cirrhosis (age, 25 to 65 years) and 27 healthy subjects of two age groups (young, 21 to 40 years; elderly, 73 to 90 years).


METHODS
Subjects received 1 gm dipyrone orally, and blood samples were drawn and urine collected over 72 hours. Plasma and urine concentrations of the four metabolites were determined by HPLC.


RESULTS
4-Methylaminoantipyrine terminal elimination half-life (t1/2 beta) in patients with cirrhosis was prolonged compared with young and elderly subjects (mean +/- SEM, 10.6 +/- 0.6 versus 3.1 +/- 0.2 and 4.9 +/- 0.6 hours, p < 0.001), and the nonrenal clearance was reduced compared with the young subjects (1.069 +/- 0.243 versus 2.165 +/- 0.154 ml/min/kg, p < 0.005). 4-Formylaminoantipyrine was undetectable in two patients and in the remaining 10 patients, t1/2 was longer than in the young subjects (26.4 +/- 4.3 versus 10.8 +/- 0.7 hour, p < 0.01), whereas the elderly had intermediate values (18.1 +/- 2.8 hours). Clearance for production of 4-formylaminoantipyrine was reduced in the patients with cirrhosis than in the young and elderly subjects (0.109 +/- 0.024 versus 0.363 +/- 0.031 and 0.340 +/- 0.053 ml/min/kg, p < 0.001). The acetylation phenotype was determined to evaluate the pharmacokinetic parameters of 4-aminoantipyrine and 4-acetylaminoantipyrine. Prolongation of the 4-aminoantipyrine t1/2 and decrease in its clearance for production was found for the patients with cirrhosis, both slow and rapid acetylators, compared with the young and elderly subjects (p < 0.01). 4-Acetylaminoantipyrine t1/2 was also prolonged for patients with cirrhosis, slow and rapid acetylators, compared with the young subjects (p < 0.005). In the slow acetylators, clearance for production of 4-acetylaminoantipyrine did not differ between the patients with cirrhosis and the young subjects (p < 0.5); however, a difference was found for the rapid acetylators (p < 0.001).


CONCLUSIONS
Our results show that the disposition of 4-methylaminoantipyrine, 4-aminoantipyrine, 4-formylaminoantipyrine, and 4-acetylaminoantipyrine is reduced by chronic liver disease after a single oral dose of dipyrone.
Zylber-Katz
E
E
Clinical Pharmacology Unit, Hadassah Univeristy Hospital, Jerusalem, Israel.
Caraco
Y
Y
Granit
L
L
Levy
M
M
D000107:Acetylation; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000675:Ampyrone / Q000493:pharmacokinetics; D016022:Case-Control Studies; D004177:Dipyrone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged
D000675:Ampyrone; D004177:Dipyrone