Anomalous Results of Studies on Drug Interaction in Man

Es, Vesell; Gt, Passananti

doi:10.1159/000136892

Cited by 6 publications

(4 citation statements)

References 6 publications

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“…However, when antipyrine and hexobarbitone were compared in the 0306-5251/82/030379-08 $01.00 same volunteers hardly any change in the elimination rate of antipyrine was observed, whereas hexobarbitone elimination rate had increased more than twice (Breimer et al, 1977). Similar observations have been made following halofenate and phenobarbitone Vesell & Passananti, 1975). In other words there seems to be a certain degree of selectivity in enhancement of rates of drug oxidation.…”

Section: Introductionsupporting

confidence: 51%

Differential effects of enzyme induction on antipyrine metabolite formation.

Danhof¹,

Verbeek²,

Boxtel³

et al. 1982

Brit J Clinical Pharma

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1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethyl-antipyrine + 3-carboxy-antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4-hydroxyantipyrine and 3-hydroxymethyl-antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.

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Section: Introductionsupporting

confidence: 51%

Differential effects of enzyme induction on antipyrine metabolite formation.

Danhof¹,

Verbeek²,

Boxtel³

et al. 1982

Brit J Clinical Pharma

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“…On the other hand cimetidine decreased clearance 0.70 fold during antipyrine induction in period II, which is what would have been expected during cimetidine treatment of non-induced subjects (D0ssing et al, 1983). Moreover, the effect of disulfiram administration for 3 days was a decrease in antipyrine clearance amounting to 0.64 times, in agreement with Vesell et al (1975). Accordingly, it appears that the slight enhancement of antipyrine elimination did not significantly affect the relative inhibiting effect of disulfiram and cimetidine in the present setting.…”

Section: Discussionsupporting

confidence: 86%

“…Enzyme inhibition was assessed by antipyrine clearance determined by a one sample method with little intraindividual variation and resistance to changes in apparent volume of distribution (D0ssing et al, 1983;Pilsgaard & Poulsen, 1984). Period I permitted investigation of the time course of the inhibiting effect of disulfiram, which has previously been shown to be maximal within 4 days of administration (Vesell et al, 1975). In the present setting antipyrine clearance was depressed further after 3 than after 1 day of disulfiram treatment.…”

Section: Discussionmentioning

confidence: 80%

Inhibition of antipyrine elimination by disulfiram and cimetidine: the effect of concomitant administration.

Loft¹,

Sonne²,

Pilsgaard³

et al. 1986

Brit J Clinical Pharma

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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

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“…Thus, a correlation coefficient of 0.30 or 0.60 or even 0.80 may have a p value of 0.001, but the relationship between the rates of elimination of the drugs is too poor for practical clinical application, since even the correlation coefficient of 0.80 yields a correct prediction in only 2 of 3 patients. Furthermore, studies on small numbers of subjects may yield a very high correlation between the elimination rates of several drugs; such relationships should be rechecked with larger groups, since some high correlations obtained with small numbers of volunteers have not been reproducible, even in the same laboratory (78). Present data suggest that the extent to which hepatic dysfunction alters rates of elimination of exogenous compounds removed by the liver varies according to the substrate.…”

Section: Methodologic Problems Predictive Values Ot Torrelatlon Coefimentioning

confidence: 77%