Our study was undertaken to determine the influence of sex and the use of oral contraceptive steroids on antipyrine clearance and metabolite formation. Our subjects were eight men (M), eight women (F), and eight women who had been using oral contraceptive steroids (OC) for at least 6 mo; all were healthy. The groups were matched for age and smoking and drinking habits. Antipyrine elimination half-life (t1/2) was longer in the OC than in the F group (12.9 +/- 2.0 and 9.7 +/- 1.7 hr) and clearance was lower (2.0 +/- 0.1 and 2.8 +/- 0.5 l/hr), while volume of distribution (Vd) was essentially the same (37.1 +/- 5.7 and 38.5 +/- 4.6 l). The M group had longer t1/2s than the F (11.8 +/- 1.2 and 9.7 +/- 1.7 hr) and greater Vds (47.1 +/- 5.4 and 38.5 +/- 4.6 l), but clearance values were the same (2.8 +/- 0.5 and 2.8 +/- 0.5 l/hr) in the two groups. Compared to the F, the three metabolic pathways of antipyrine appeared to be inhibited in the OC group. Partial clearances for production for the F and OC groups were (l/hr); norantipyrine (NORA) 0.70 +/- 0.13 and 0.42 +/- 0.12, 4-hydroxyantipyrine (OHA) 1.19 +/- 0.37 and 0.83 +/- 0.25, and 3-hydroxymethylantipyrine (HMA) 0.45 +/- 0.10 and 0.33 +/- 0.09. Partial clearance for production in the F group was higher than in the M for OHA (1.19 +/- 0.37 and 0.78 +/- 0.15 l/hr) and NORA (0.07 +/- 0.13 and 0.56 +/- 0.13 l/hr), but not for HMA (0.45 +/- 0.10 and 0.40 +/- 0.05 l/hr). In the F group, total metabolite recovery was higher than the M. We conclude that sex and OC steroids have differential effect on the several metabolic pathways of antipyrine.
The effect of different doses on the rate of metabolism of theophylline in rats was investigated. After doses of 52 or 115 mg/kg, the initial concn. decayed according to a first-order process with an apparent half-life of about four hours. However, after four to eight hours the slope of the curves declined, resulting in elimination half-lives of about 70 min. Similar half-lives of 70 min were also found after doses of 6 or 11 mg/kg. The AUC increased disproportionately with dose, indicating capacity-limited elimination. No differences were observed in capacity-limited elimination of the two major metabolites of theophylline: the ratio between the amounts of 1,3-dimethyluric acid and 1-methyluric acid formed was independent of the dose of theophylline. The initial apparent first-order decay after higher doses resulted from a combination of capacity-limited metabolism and compensatory increased diuresis of unchanged theophylline. It is concluded that linear pharmacokinetics of theophylline in rats apply only to doses not exceeding 10 mg/kg.
The influence of pretreatment of rats with 9-hydroxyellipticine and 3-methylcholanthrene on different enzymes of the hepatic mixed-function oxidase system were studied using antipyrine as model compound. Antipyrine half-lives and clearances were estimated in blood, and the metabolite profile was determined in urine. 3-Methylcholanthrene treatment resulted in an increase in antipyrine clearance from 17 to 75 ml/min per kg. Partial clearance of formation of 4-hydroxyantipyrine was selectively increased from 3.9 to 28.2 ml/min kg, whereas clearance of 3-hydroxymethylantipyrine was decreased from 3.2 to 1.2 ml/min per kg. Norantipyrine formation was increased from 2.7 to 7.2 ml/min per kg, while 4,4'-dihydroxyantipyrine formation was unchanged. 9-Hydroxyellipticine treatment resulted in no change in the total clearance, and only the clearance of 4,4'-dihydroxyantipyrine was decreased, from 2.5 to 1.5 ml/min per kg. After pretreatment with 3-methylcholanthrene, 9-hydroxyellipticine treatment resulted in a selective decrease in the clearances of 4-hydroxyantipyrine, from 28.2 to 15.8 ml/min per kg, and of 4,4'-hydroxyantipyrine, from 3.8 to 1.6 ml/min per kg. From these results it is concluded, that 9-hydroxyellipticine is a selective inhibitor of the activity of some of the cytochrome P-450s involved in antipyrine metabolism, though this inhibition does not effect all of these enzymes, nor is it restricted to polycyclic hydrocarbon-induced activity. These results further substantiate the value of antipyrine as a model substrate, for they indicate that the formation of all four metabolites of antipyrine in rats is mediated by different (iso-)enzymes.
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