Differential Effects of GPA 1851 on Hepatic Microsomal Drug Metabolism Dependent on Dosage and Time of Sacrifice

Es, Vessell; Cj, Lee; Gt, Passananti; Ca, Shively

doi:10.1159/000136337

Cited by 10 publications

(3 citation statements)

References 3 publications

(3 reference statements)

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“…The importance of the timing of drug administration in analyzing effects on drug disposition is illustrated in Study II (Tables II and III). 16 Thin-layer chromatography of capsule quinine (U.S.P. In this study the antipyrine was given on day 4, and its administration coincided with the determination of the plasma quinine decay curve.…”

Section: Discussionmentioning

confidence: 99%

Quinine‐induced alterations in drug disposition

Berlin

Stackman

Vesell

1975

Clin Pharma and Therapeutics

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In normal volunteers, chronic quinine administration shortened plasma antipyrine half-life and significantly increased the intraindividual correlation between the disposition of quinine and antipyrine. Decreased plasma antipyrine half-life appears to be due to a quinine-induced enhancement of antipyrine metabolism. A dose-dependent prolongation of plasma quinine half-life was observed and attributed primarily to an increased apparent volume of distribution of quinine, although our data did not permit separation of an effect on quinine metabolism from an effect on quinine distribution between the peripheral and central compartments. Plasma protein binding of quinine was similar at both the low and high doses of quinine. Studies in dogs given quinine intravenously revealed a biphasic plasma decay curve compatible with a 2-compartment open model for quinine disposition. Dose dependence of plasma quinine half-life in the dog after intravenous quinine eliminated altered gastrointestinal absorption of quinine as a cause for the dose dependence of plasma quinine half-life. These studies illustrate the importance of such conditions as dose and time of administration in determining the type and magnitude of interaction observed between drugs.

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Section: Discussionmentioning

confidence: 99%

Quinine‐induced alterations in drug disposition

Berlin

Stackman

Vesell

1975

Clin Pharma and Therapeutics

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“…The accompanying paper by Vesell et al (13) also shows the effects of GPA 1851 on hepatic enzymes under in vitro conditions. Furthermore, those findings draw attention to the fact that the terms 'enzyme inhibition' and 'en zyme induction' must be used with great care since the experimental conditions may have profound effects on the results.…”

Section: Discussionmentioning

confidence: 95%

Interaction of the Imidazolone Derivative GPA 1851 with Hepatic Microsomal Drug Metabolism

Zak¹,

Gilleran²,

Lukas³

1972

Pharmacology

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The biological disposition of GPA 1851, a compound with anti-inflammatory proper ties, has been investigated in several species. During these studies a dramatic prolongation of barbitu rate sleeping time was observed in rats, dogs and monkeys pretreated with GPA 1851. Both in vivo and in vitro findings indicated that the interaction of GPA 1851 with barbiturates was a result of its inhibition of hepatic microsomal enzyme activity. However, further studies demonstrated that repeated dosing with GPA 1851 abolished the inhibitory effect of a single dose.

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“…For example, our study on GPA 1851 revealed that this com pound could produce three different effects: inhibition, induction or no change of hepatic microsomal mixed function oxidase activity (12).…”

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confidence: 96%

Anomalous Results of Studies on Drug Interaction in Man

Vesell¹,

Passananti²,

Glenwright³

1975

Pharmacology

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Disulfiram inhibited antipyrine metabolism reproducibly in three experiments utilizing three different groups of normal human volunteers. In these experiments disulfiram in a dose of 3.5 mg/kg body weight was given orally twice daily for 4 consecutive days and in two subsequent experiments for 10 consecutive days. In each experiment the mean antipyrine half-life was prolonged and the mean metabolic clearance rate of antipyrine was shortened by disulfiram. Large interindividual variations occurred; one volunteer with a very short initial plasma antipyrine half-life shortened, rather than prolonged, his antipyrine half-life after 10 days of disulfiram. In the first 10-day study the apparent volume of distribution of antipyrine was significantly increased in each volunteer after disulfiram administration, whereas in the second 10-day study, disulfiram failed to alter this value. Another anomalous result concerned attempts to determine whether a correlation existed between the initial antipyrine half-life and the percent change in this value produced by disulfiram administration. A significant correlation occurred in the initial 10-day study (r = 0.71, p < 0.05), whereas neither in the second 10-day study (r = 0.20, p > 0.05) nor in the 4-day study (r = 0.57, p > 0.05) was a significant correlation observed. Each of the three studies revealed no significant correlation between the initial metabolic clearance rate of antipyrine and the percent change in this value produced by disulfiram administration.

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Differential Effects of GPA 1851 on Hepatic Microsomal Drug Metabolism Dependent on Dosage and Time of Sacrifice

Cited by 10 publications

References 3 publications

Quinine‐induced alterations in drug disposition

Quinine‐induced alterations in drug disposition

Interaction of the Imidazolone Derivative GPA 1851 with Hepatic Microsomal Drug Metabolism

Anomalous Results of Studies on Drug Interaction in Man

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