1 The effect of liver cirrhosis on plasma clearance and metabolite profile of i.v. administered antipyrine was studied in 23 patients wth alcoholic liver cirrhosis (age years) and 17 healthy subjects (age 28-55 years). 2 Liver volume was also measured and was found to be larger in patients than in controls, mean values being 1.86 and 1.36 1 respectively. 3 The elimination half-life of antipyrine in patients with alcoholic liver cirrhosis was significantly longer than in the healthy subjects (P < 0.001). Mean values were 39.9 and 10.1 h respectively. 4 Alcoholic liver cirrhosis had no effect on the apparent volume of distribution of antipyrine, but antipyrine plasma clearance was substantially reduced in the patients.Mean clearance values (ranges) were 13.5 (9.3-22.8) ml/min in the patients and 49.3 (31.1-103) m/min in healthy subjects. 5 Normalization of antipyrine plasma clearance for liver volume resulted in an only slightly increased distinction between patients and healthy subjects, mean values (ranges) being 7.8 (3.3-13.0) ml min-' 171 and 36.1 (21.9-35.9) ml min-1 1-1 respectively. 6 The cumulative renal excretion of 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was significantly lower in patients with alcoholic liver cirrhosis than in healthy subjects, as was the total recovery of antipyrine and major metabolites from urine. Mean values were 15.0, 8.4 and 41.2% of dose in the patients respectively and 24.3, 25.8 and 68.9% of dose in the control subjects. Excreted amounts of total and unconjugated 3-hydroxymethylantipyrine (HMA) and of unchanged antipyrine were the same in the two groups.7 Clearance for production of all three major metabolites of antipyrine (CLm) was markedly reduced in patients with alcoholic cirrhosis, while the rate of formation of NORA was significantly more reduced than the rates of formation of OHA and HMA.Mean values for CLOHA, CLNORA and CLHMA were: 2.6, 1.4 and 2.0 ml/min respectively in the patients and 12.9, 13.2 and 7.9 ml/min in the healthy subjects. 8 The results of this study show that antipyrine metabolism is severely impaired in patients with alcoholic liver cirrhosis. However, as the rates of formation of antipyrine metabolites were not reduced to the same extent, different isoenzymes of the cytochrome P-450 system may be differently affected by alcoholic liver cirrhosis.

1 Oxidative metabolism of antipyrine (AP) was compared in 11 elderly (> 65 years) and 12 young (< 40 years) volunteers. All subjects were non-smokers, consumed little if any alcohol and were in good health. 2 After a single dose of AP 500 mg, its clearance from saliva and profiles of the parent drug and its major metabolites in urine were determined using high-performance liquid chromatography. 3 Mean total AP clearance from saliva was lower in the elderly (P < 0.05). Mean weightnormalised volume of distribution was also smaller (P < 0.01) so that elimination half-life in the elderly was not significantly different from that in the young. 4 The percentage dose excreted in 48 h urine as norantipyrine (NORA) and its clearance for production were lower in the elderly (P < 0.001 and P < 0.01 respectively). Urinary 3-hydroxymethylantipyrine (HMA) and free antipyrine were present in greater quantities in 48 h urine in the elderly (P < 0.001 and P < 0.05) while the amounts of 4-hydroxyantipyrine (OHA) were almost identical in the two age groups. 5 The findings suggest that there is a selective impairment of N-demethylation in the elderly which may have important implications for dosage of elderly patients with drugs metabolised by this route.

The influence of an 8‐day therapy with rifampicin (600 mg daily) was studied on antipyrine plasma clearance and metabolite formation in seven patients with tuberculosis (age 18‐79 years), who were also treated with isoniazid and pyrazinamide. After rifampicin treatment the elimination half‐life of antipyrine had decreased in all patients from 12.9 +/‐ 5.0 to 8.8 +/‐ 2.0 h (P less than 0.05). Antipyrine clearance had increased from 2.2 +/‐ 0.9 to 2.9 +/‐ 0.7 l/h (P less than 0.05), while no change in apparent volume of distribution was observed. The increase in antipyrine clearance was primarily due to a selective increase in the rate of formation of norantipyrine by 80% from 6.9 +/‐ 3.4 to 12.4 +/‐ 3.4 ml/min. Rifampicin seems to induce preferentially the cytochrome P‐450 (iso‐) enzyme(s) involved in the demethylation of antipyrine to norantipyrine. Other pathways of antipyrine metabolism were hardly affected. This provides further evidence for the involvement of different iso‐enzymes of the cytochrome P‐450 system in antipyrine metabolism in man.

The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation was studied by giving 500 mg antipyrine to 14 extensive and 10 poor metabolizers of debrisoquine. The pharmacokinetics of antipyrine were determined on the basis of the saliva concentration time curve and the cumulative urinary excretion of 4-hydroxyantipyrine, norañtipyrine, 3-hydroxymethyl-antipyrine, and 3-carboxyantipyrine was measured for 32 h following drug administration. Antipyrine elimination half-life, volume of distribution, and total clearance were almost equal for the two groups. Significant differences in the excretion of antipyrine metabolites were not observed, except for 3-hydroxymethyl-antipyrine which was excreted in poor metabolizers about 30% less than in extensive metabolizers (p < 0.01). However, this difference only reached borderline significance (p < 0.1) when clearance values for production of this metabolite were calculated. It is concluded that different species of the drug-oxidizing enzymes (cytochrome P-450 system) are involved in the metabolism of debrisoquine and antipyrine. Possibly the enzyme responsible for hydroxylating debrisoquine is partly involved in the formation of 3-hydroxymethyl-antipyrine.

Antipyrine salivary clearance and half-life and the rate of formation of three principal metabolites of antipyrine (4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine) were assessed in nine children with congenital adrenal hyperplasia, six of whom were salt-losers and three of whom were non-salt-losers. No differences were found in comparison with data obtained in normal children.