Four healthy subjects were investigated weekly for 14 weeks by the antipyrine one sample saliva test, the 48-h urinary excretion of major antipyrine metabolites and the 2-h aminopyrine breath test before, during and after stimulation and inhibition of drug metabolism with phenobarbital and cimetidine, respectively. The phenobarbital-induced enhancement of antipyrine clearance (1.33-2.03 times) and of the aminopyrine breath test (0.94-1.19 times) occurred one week after beginning drug administration and persisted for 10 days after its cessation. The cimetidine-related inhibition of antipyrine clearance (0.62-0.85 times) and of the aminopyrine breath test (0.52-0.93 times) was observed 24 h after beginning cimetidine administration and subsided within two days after the last dose. During enhancement and inhibition the clearance of antipyrine to 3-hydroxymethyl-, 4-hydroxy- and norantipyrine varied as the total antipyrine clearance. The intraindividual variation in antipyrine clearance was 6-8%, and the corresponding variation in urinary excretion of antipyrine metabolites was 10-20%. It is concluded that the influence of phenobarbital and cimetidine on hepatic microsomal enzyme activity can be monitored simply by measurement of the blood concentration of the drug. Whether this simple relationship applies to other microsomally mediated drug interactions requires further evaluation.
Antipyrine (AP) clearance was determined from AP plasma decay in 57 rats at various times after partial hepatectomy. This value for AP clearance correlated closely (r = 0.99) to AP clearance estimated from a single plasma AP concentration measured 5 h after AP administration. An AP apparent volume of distribution was taken as 0.66 liters per kilogram body weight. The error introduced by estimating AP apparent volume of distribution as 0.66 times body weight was negligible, even when only a single plasma sample for AP concentration served to calculated AP clearance. This single sample method is especially applicable to large scale investigations, acute and chronic, where evaluation of hepatic microsomal function is needed, but time and sampling facilities are limited.
We investigated the effect of concomitantly administered disulfiram and cimetidine on antipyrine elimination. On day 1, 2, 4 and 6 of two periods of 6 days one sample antipyrine saliva clearance (APC) was measured in nine healthy volunteers. From day 2 to 6 of period I disulfiram 400 mg dayf1 was administered and on day 5 and 6 cimetidine 1000 mg day-1 was added. In period II only cimetidine was given (on days 5 and 6). On day 4 of period II APC was increased 1.3 fold, probably due to self-induction by repeated antipyrine administration. Taking this into account disulfiram and cimetidine separately decreased APC 0.64 and 0.70 times, respectively. When both inhibitors were given APC was reduced 0.52 times. The results suggest that the effects of cimetidine and disulfiram on antipyrine elimination are additive.Keywords disulfiram cimetidine antipyrine inhibition of drug metabolism
DefinitionThe Working Group was originally asked t o address the potential carcinogenic risk from exposure to outdoor air, drinking water, sunlight and radon gas. During the work it was realized that environmental tobacco smoke should also be considered. The group did not attempt, however, to make a comprehensive review of indoor air.
ABSTRACT— We investigated antipyrine clearance and urinary excretion of 4‐hydroxyantipyrine, 3‐hydroxymethylantipyrine and nor‐antipyrine in rats after 70% partial hepatectomy. Antipyrine clearance recovered more slowly than liver weight but after 240 h both liver weight and antipyrine clearance had reached control values. During hepatic regeneration conversion of antipyrine to the three major metabolites was reduced, conversion to 3‐hydroxymethylantipyrine being reduced more than conversion to the other metabolites. Antipyrine clearance was closely correlated to liver weight (r = 0.81), indicating a close relation between the functional hepatic mass and the liver weight during hepatic regeneration.
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