Assessment and Prediction of In Vivo Oxidative Drug Metabolizing Activity

Breimer, D. D.; Vermeulen, Nico; Danhof, Meindert; Teunissen, M. W. E.; Joeres, R.; Graaff, M. van der

doi:10.1007/978-1-4613-2799-8_17

Cited by 15 publications

(7 citation statements)

References 38 publications

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“…Antipyrine is frequently used as a model drug to assess the influence of environmental factors (like induction by drugs) on hepatic oxidative drug-metabolizing enzyme activity (Vestal et al, 1975;Vesell, 1979 (Danhof & Breimer, 1979b;Danhof et al, 1982b;Teunissen et al, 1983a;Breimer et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Influence of rifampicin treatment on antipyrine clearance and metabolite formation in patients with tuberculosis.

Teunissen¹,

Bakker²,

Meerburg‐Torren³

et al. 1984

Brit J Clinical Pharma

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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.

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Section: Introductionmentioning

confidence: 99%

Influence of rifampicin treatment on antipyrine clearance and metabolite formation in patients with tuberculosis.

Teunissen¹,

Bakker²,

Meerburg‐Torren³

et al. 1984

Brit J Clinical Pharma

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“…Studies have been carried out in an attempt to correlate drugs which are metabolised by the same P-450s (28,29). They suggest heptabarbitone and hexobarbitone are metabolised by the same isoenzymes as that which produces HMA, and that benzo(a)pyrene, caffeine and theophylline are acted upon by the P-450 which is responsible for OHA formation.…”

Section: Discussionmentioning

confidence: 99%

Effect of tacrine hydrochloride on hepatic drug metabolism

Danbury

Eccles

Ford

et al. 1999

Eur. J. Drug Metab. Pharmacokinet.

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The aim was to assess tacrine hydrochloride (THA) as an inhibitor of rat hepatic oxidative enzymes. A model of hepatic microsome oxidative metabolism was established using antipyrine (AP) incubated with NADPH. AP and its metabolites, 3-hydroxymethyl antipyrine (HMA). 4-hydroxy antipyrine (OHA) and norantipyrine (NORA) were measured by high performance liquid chromatography (HPLC). Aliquots of 200, 400 and 600 microg/ml antipyrine were incubated with the microsomal preparation alone, with 20 microg/ml cimetidine or with 40, 80 or 200 microg/ml THA. Cimetidine inhibited HMA production by 35-38% (P<0.001) and OHA production by 49-52% (P<0.001). Incubation with the 3 concentrations of THA inhibited HMA production by 17%, 24% and 41% (P<0.001) and OHA production by 52%, 55% and 79%, respectively (P<0.001). NORA was identifiable when antipyrine was incubated with NADPH alone, but could not be identified after incubation with either cimetidine or THA. This study has shown that THA causes the inhibition of AP metabolism to HMA, OHA and possibly NORA. We suggest THA is an inhibitor of three different hepatic microsomal cytochrome P-450 enzyme sub-families.

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“…Many efforts have been made to acquire quantitative information on this capacity by measuring the in vivo pa rameters of endogenous compounds or the rates of elimination from plasma of exoge nous compounds [Vesell, 1979;Danhof, 1980;Breimer et al, 1983], One of the widely used model drugs in the assessment of hepatic drug metabolizing activity in ani mals and also in man is hexobarbital [Bush and Weller, 1972;Holcomb et al, 1974], Hexobarbital is completely metabolized in the liver via the mixed function mono-oxy genase system and it is generally believed that the duration of its hypnotic action is a reasonable reflection of its overall rate of metabolism [Bush and Weller, 1972], Recently, however, hexobarbital was shown to undergo first-pass elimination in the rat to an extent of about 70% after oral application. Under such conditions the sys temic clearance, as estimated upon intrave nous administration, is affected by liver blood flow as well as by the metabolizing enzyme activity of the liver [Gibaldi and Perrier, 1974;Wilkinson and Shand, 1975], In order to estimate the intrinsic hepatic clearance, merely reflecting the metabolizing capacity, the oral route of administration should be applied [Vermeulen, 1980], Doses of 50-100 mg/kg as usually administered in previous rat experiments [Holcomb et al, 1974;Breimer and van Rossum, 1974;Drew et al, 1977;Richter et.…”

Section: Introductionmentioning

confidence: 99%

Influence of the Rate of Hepatic Portal Vein Infusion on Hexobarbital Pharmacokinetics in the Rat

1988

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Pharmacokinetic parameters of hexobarbital were estimated in rats after hepatic portal infusion of a 10-mg dose. Infusion during 10 min resulted in an area under the blood concentration-time curve (AUC) of 556 ± 83 μg·min/ml and a clearance of 83 ± 13 ml/min·kg, whereas infusion of the same dose during 40 min resulted in values of 272 ± 36 μg·min/ml and 169 ± 30 ml/min·kg, respectively (mean values ± SD, n = 3). Infusion during 15 and 20 min provided intermediate values. The decrease of the AUC and the increase of the blood clearance of hexobarbital following decreasing infusion rates clearly indicate nonlinear pharmacokinetics related to the hepatic inflow concentration of hexobarbital.

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Assessment and Prediction of In Vivo Oxidative Drug Metabolizing Activity

Cited by 15 publications

References 38 publications

Influence of rifampicin treatment on antipyrine clearance and metabolite formation in patients with tuberculosis.

Influence of rifampicin treatment on antipyrine clearance and metabolite formation in patients with tuberculosis.

Effect of tacrine hydrochloride on hepatic drug metabolism

Influence of the Rate of Hepatic Portal Vein Infusion on Hexobarbital Pharmacokinetics in the Rat

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