Measurement of urinary 6-?-hydroxycortisol excretion as an in vivo parameter in the clinical assessment of the microsomal enzyme-inducing capacity of antipyrine, phenobarbitone and rifampicin

Ohnhaus, E. E.; Park, B. K.

doi:10.1007/bf00609878

Cited by 181 publications

(83 citation statements)

References 24 publications

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“…There are two distinct oxidative pathways for diazepam, one to desmethyldiazepam, the major In the present study an induction of the liver microsomal enzyme system was found following antipyrine administration for a period of 14 days based on the changes in the in vivo parameters measured. The extent of enzyme induction was similar to that found in other studies using antipyrine as an inducing agent (Davies, Simmons, Dordoni & Williams, 1974;Whitfield, Moss, Neale, Orme & Breckenridge, 1973;Ohnhaus, Martin, Kinser & Colombo, 1977;Ohnhaus & Park, 1979); antipyrine clearance, y-glutamyl-transpeptidase,, D-glucaric acid and 6-,B-hydroxycortisol urinary excretion showed similar increases. metabolite, and other to 3-hydroxydiazepam.…”

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

The effect of enzyme induction on diazepam metabolism in man.

Ohnhaus¹,

Park²,

Colombo³

et al. 1979

Brit J Clinical Pharma

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1 The elimination and metabolism of diazepam in man was investigated following the induction of the liver microsomal enzyme system by antipyrine. 2 Seven healthy volunteers were given 1200 mg antipyrine as an inducing agent for a period of 14 days. Before and after the induction period the elimination of diazepam and desmethyldiazepam was measured in the plasma by gaschromatography. As parameters of liver microsomal enzyme activity, antipyrine elimination and gamma‐glutamyl‐ transpeptidase in the plasma, D‐glucaric acid and 6‐beta‐ hydroxycortisol urinary excretion were measured on both occasions. 3 Following the induction period most parameters of microsomal enzyme activity measured were significantly changed indicating an increase of the microsomal enzyme system. The elimination of diazepam was significantly altered having a half‐life of 37 h before and 18 h afterwards combined with a significant increase in total body clearance after the induction period, although the volume of distribution remained unaltered. The formation of the main metabolite N‐ desmethyldiazepam was not changed, but its elimination was increased having a half‐life of 139 or 58 h respectively. 4 The elimination of unchanged diazepam and desmethyldiazepam is significantly increased by the induction of the liver microsomal enzyme system using antipyrine as an inducing agent in healthy volunteers, which might be important under certain clinical conditions.

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Section: Discussionsupporting

confidence: 87%

“…Measurement of y-glutamyl-transpeptidase. The y-glutamyl-transpeptidase in the plasma was measured by the method of Szasz (1969 (Ohnhaus & Park, 1979).…”

Section: Volunteersmentioning

confidence: 99%

The effect of enzyme induction on diazepam metabolism in man.

Ohnhaus¹,

Park²,

Colombo³

et al. 1979

Brit J Clinical Pharma

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“…drug metabolism in humans [1,2] and is known to Isoniazid, another anti-tuberculosis drug, inhibits interact with a number of drugs such as warfarin, hepatic oxidative metabolism of a number of drugs digitoxin, dapsone, chlorpropamide, metoprolol, theosuch as phenytoin (metabolised by CYP2C9), carba- [3,[14][15][16]. This suggests that inhibition of oxidative drug metabolism by isoniazid is not selective [17].…”

Section: Introductionmentioning

confidence: 99%

Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man.

Wanwimolruk

Kang

Coville

et al. 1995

Brit J Clinical Pharma

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The effect of rifampicin and isoniazid pretreatment on the pharmacokinetics of quinine after a single oral dose (600 mg quinine sulphate) was studied in nine healthy young Thai male volunteers using a three-way randomized crossover design. Subjects were studied over three 2 day periods, during which they received no pretreatment, or pretreatment with daily 600 mg p.o. rifampicin for 2 weeks, or isoniazid 300 mg p.o. daily for 1 week, prior to quinine administration. The mean (+ s.d.) clearance (CL/F) of quinine coadministered with rifampicin (0.87 ± 0.35 1 h-1 kg-') was significantly greater than that of quinine alone (0.14 ± 0.05 1 h-1 kg-'). The mean difference in clearance from the control treatment was 0.73 1 h-1 kg-', with 95% confidence interval (C.I.) of 0.48 to 0.98. The unbound clearance (CLu/F) of quinine, which reflects the activity of the drug-metabolizing enzymes, was considerably greater (6.9-fold) in subjects when rifampicin was coadministered with quinine than that of quinine alone (6.9 ± 3.6 vs 1.0 ± 0.5 1 h-1 kg-'; the 95% C.I. for the mean difference was 3.3 to 8.5). The mean elimination half-life of quinine when coadministered with rifampicin (5.5 ± 3.0 h) was significantly shorter than when quinine was given alone (11.1 ± 3.0 h; the 95% C.I. for the mean difference was -8.6 to -2.6). In contrast to rifampicin, pretreatment for 1 week with 300 mg oral isoniazid had no significant effects on the pharmacokinetics of quinine. These results indicate that rifampicin pretreatment caused a marked increase (6.2-fold) in the clearance of quinine, possibly due to enzyme induction. The extent to which the elimination of quinine is enhanced by the concomitant administration of rifampicin is likely to have important clinical consequences. Although the clinical significance of these findings is unknown, they indicate the need for caution in the administration of quinine to patients who are concurrently taking rifampicin as an anti-tuberculosis medication.

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“…Other inducers include griseofulvin 121,123,124 and rifampicin 125,126 . Rifampicin is one of the most potent inducers of microsomal enzyme activity.…”

Section: Drugs Causing Enzyme Inductionmentioning

confidence: 99%

“…The reduction is suggested to be caused by accelerated metabolism of anticoagulant secondary to stimulation of hepatic microsomal enzyme activity 4 . Meprobamate 121,122 and methaqualone 107 appear to have no effect on anticoagulants.Other inducers include griseofulvin 121,123,124 and rifampicin 125,126 . Rifampicin is one of the most potent inducers of microsomal enzyme activity.…”

mentioning

confidence: 99%

Interactions of Warfarin

Rehulková¹

2001

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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In this article, the author reviews and updates the basis of interactions with warfarin, illustrated with appropriate examples. The interactions with drugs, medicinal herbs and foods are summarised. 28Cholestyramine binds vitamin K in the gut, thus preventing its absorption 18 . It also decreases the absorption and may interrupt the enterohepatic recirculation of warfarin, resulting in a reduced anticoagulant effect 19,20 .Colestipol does not affect the absorption of warfarin. When colestipol is administered with warfarin, no depressant effects on blood levels are seen 21 . Drugs affecting receptor sensitivityEstrogens increase the synthesis of various clotting factors and may thus reduce the effect of anticoagulants 22, 23 . Oral contraceptives increase clotting factor concentrations and inhibit warfarin metabolism. The net effect depends on balance between these factors. Oral contraceptives are generally contraindicated in most patients taking warfarin since they are trombogenic 1, 24 .Steroids with anabolic or androgenic properties, such as oxymetholone 25, 26, 27 , stanozolol 28, 29 and danazol 30, 31, 32 , may potentiate the action of warfarin allegedly by reducing clotting factor synthesis. The 17-alpha-alkylated steroids appear to be more likely to induce this reaction than the non-substituted steroids 25, 26, 27, 33 . However, there has been a report of topically applied testosterone, which does not have 17-alpha-alkyl substituent, enhancing warfarin 34 .Diuretics may antagonise the action of warfarin by two pharmacodynamic mechanisms 18 : (a) patients in cardiac failure have impaired clotting factor synthesis due to hepatic congestion -correction of this state leads to increased clotting factor synthesis; (b) diuretics also reduce the plasma volume producing an increased concentration of clotting factors which may alter the anticoagulant effect of warfarin 35 . Chlorthalidone 36 and spironolactone 35 have both been associated with a reduction of warfarin activity probably as a consequence of diuresis concentrating the circulating clotting factors. Bumetanide, furosemide and thiazides appear to have no effect on warfarin 23 .Certain cephalosporines, such as cefotetan, cefamandole, cefoperazone, or moxalactam may cause marked hypoprothrombinemia and/or prolonged bleeding time at concurrent use with warfarin 38, 39, 40, 41 . The main mechanism of interaction consists in decreasing synthesis of vitamin K-dependent clotting factors.Clofibrate may potentiate warfarin action, probably by altering receptor sensitivity 23, 37 . Although clofibrate displaces warfarin from albumin binding sites this does not appear to be a principal mechanism of the interaction 42 .Drugs altering thyroid function may affect anticoagulant control, since rates of synthesis and degradation of clotting factors are dependent on thyroid function 7 . Thyroid compounds do enhance the activity of oral anticoagulants by increased metabolism of clotting factors 12 . Dextrothyroxine increases the anticoagulant effect of warfarin ...

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Measurement of urinary 6-?-hydroxycortisol excretion as an in vivo parameter in the clinical assessment of the microsomal enzyme-inducing capacity of antipyrine, phenobarbitone and rifampicin

Cited by 181 publications

References 24 publications

The effect of enzyme induction on diazepam metabolism in man.

The effect of enzyme induction on diazepam metabolism in man.

Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man.

Interactions of Warfarin

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