The effects of phenobarbital, chloral betaine, and glutethimide administration on warfarin plasma levels and hypoprothrombinemic responses in man

MacDonald, Murdo G.; Robinson, Donald S.; Sylwester, David; Jaffe, Julian J.

doi:10.1002/cpt196910180

Cited by 91 publications

(17 citation statements)

References 3 publications

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“…Glutethimide has been shown to cause hepatic microsomal enzyme induction in rats (Conney, 1967), and to interact with warfarin in man (Corn, 1966;MacDonald et al, 1969;Udall, 1975). Patients tolerant to glutethimide metabolise the drug more rapidly than normal persons (Schmid, Cornu, Imhof & Kebrele, 1964) and long term treatment has been associated with osteomalacia (Greenwood, Prunty & Silver, 1973).…”

Section: Discussionmentioning

confidence: 99%

“…It is highly lipid-soluble and its main route of elimination from the body is through hepatic metabolism (Curry, Riddall, Gordon, Simpson, Binns, Rondel & McMartin, 1971). It has been shown to shorten warfarin plasma half life (Corn, 1966), to cause a fall in steady state plasma warfarin levels (MacDonald, Robinson, Sylwester & Jaffe, 1969) and to decrease the hypoprothrombinaemic effect of warfarin (Udall, 1975) by hepatic microsomal enzyme induction. Detailed studies in man on the potency of glutethimide as an enzyme inducing agent have not hitherto been performed.…”

Section: Introduictionmentioning

confidence: 99%

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The features of hepatic enzyme induction with glutethimide in man.

Jackson¹,

Homeida²,

Roberts³

1978

Brit J Clinical Pharma

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1 Sequential measurements of D‐glucaric acid excretion were made in six healthy volunteers before, during and after 3 weeks' daily medication with glutethimide 500 mg. 2 There was a rapid rise in D‐glucaric acid excretion within 2 days of starting medication and a rapid decline when it was stopped. 3 Antipyrine clearance and indocyanine green clearance were measured before and at the end of the 3 weeks' medication. 4 There was a 55% increase in antipyrine clearance but no change in indocyanine green clearance. 5 There was no correlation between antipyrine clearance and D‐glucaric acid excretion. 6 Glutethimide causes rapid enzyme induction in man without concomitant rise in hepatic blood flow.

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Section: Discussionmentioning

confidence: 99%

Section: Introduictionmentioning

confidence: 99%

The features of hepatic enzyme induction with glutethimide in man.

Jackson¹,

Homeida²,

Roberts³

1978

Brit J Clinical Pharma

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“…The effect of barbiturates on anticoagulant therapy with warfarin is well known (Conney, 1967). Other drugs known to cause induction in man when given in therapeutic doses include phenylbutazone (Poland et al, 1970), hydrocortisone , glutethimide (McDonald et al, 1969), antipyrine , and hence dichloralphenazone, rifampicin (Remmer, 1976), and ethanol (Rubin and Lieber, 1968). Undoubtedly others will be identified.…”

Section: Changes In Endogenous Substances As Indices Of Microsomal Enmentioning

confidence: 99%

Enzyme Induction by Drugs

Marshall

1978

Ann Clin Biochem

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SUMMARY The properties of the hepatic microsomal, drug detoxicating, enzyme system are reviewed with particular reference to its inducibility. Induction is modified by various factors of which the diet is particularly important. A theoretical model system for induction has been proposed and this is discussed. There are a number of methods for assessing microsomal enzyme induction in man, none of which is ideal. Nevertheless, induction is a well recognised phenomenon in man and has a bearing on the metabolism of a number of endogenous substances. The effect of induction on steroid metabolism and the relationship between inducers, vitamin D, and metabolic bone disease is discussed. Bilirubin metabolism is affected by changes in microsomal enzyme activity and inducers have been used therapeutically in some cases of hyperbilirubinaemia. The relationship between drugs and the hepatic porphyrias is reviewed. The hepatic microsomal enzyme system is but one of many inducible enzymes and the role of induction in general in metabolic regulation is emphasised.

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“…Amobarbital 112 , phenobarbital 107 , secobarbital 107 has also been reported to diminish pharmacological activity of warfarin. A number of other hypnosedatives and anticonvulsant drugs such as gluthethimide 107,113,114 , carbamazepine 115,116,117,118 and phenytoin 119 induce metabolism of warfarin. Benzodiazepines do not interact significantly with warfarin 1 .…”

Section: Drugs Causing Enzyme Inductionmentioning

confidence: 99%

Interactions of Warfarin

Rehulková¹

2001

BIOMED PAP

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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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The effects of phenobarbital, chloral betaine, and glutethimide administration on warfarin plasma levels and hypoprothrombinemic responses in man

Cited by 91 publications

References 3 publications

The features of hepatic enzyme induction with glutethimide in man.

The features of hepatic enzyme induction with glutethimide in man.

Enzyme Induction by Drugs

Interactions of Warfarin

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