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Biomedical subjects

M Orme

Publications and source records attributed to M Orme.

65 records · Page 4Linked to original sources
PubMed1974

Warfarin. Stereochemical aspects of its metabolism and the interaction with phenylbutazone.

An examination of the metabolic fate of the R and the S isomers of warfarin revealed that the two isomers were metabolized by different routes. R warfarin was oxidized to 6-hydroxywarfarin and was reduced to the (R,S) warfarin alcohol. In contrast, S warfarin was oxidized to 7-hydroxywarfarin and was reduced to the (S,S) warfarin alcohol. S warfarin was also oxidized to 6-hydroxywarfarin. These observations suggested that interactions between warfarin and other drugs might be manifest stereo-specifically, i.e., have a different effect on the isomers of warfarin, so a series of experiments were conducted with each isomer of warfarin, before and after phenylbutazone. The plasma clearance of S warfarin was slowed from 3.1 to 1.1% per h in one subject and from 2.3 to 1.6% per h in another. In contrast, the clearance of R warfarin was increased from 1.5 to 3.0% per h and from 0.9 to 1.6% per h in two subjects after phenylbutazone. The rate of clearance of racemic warfarin was unaffected by phenylbutazone; the depression of the rate of clearance of the S isomer masked the stimulation of the clearance of the R isomer. Since S warfarin is five times more potent an anticoagulant than R warfarin, it is concluded that inhibition of the metabolism of S warfarin provides one mechanism for the augmented anticoagulation which follows phenylbutazone.

Blood Coagulation↗
PubMed1973

Changes in plasma -glutamyl transpeptidase activity associated with alterations in drug metabolism in man.

A significant rise in plasma gamma-glutamyl transpeptidase activity (GGT) was observed on 13 out of 14 occasions on which patients on long-term treatment with the oral anticoagulant warfarin were given amylobarbitone, quinalbarbitone, or phenazone (antipyrine) for 30 days. In 13 of these 14 studies there was evidence that drug administration had stimulated the rate of warfarin metabolism. One patient showed no increase in plasma GGT activity, yet a significantly increased rate of warfarin metabolism, and another patient showed an increase in plasma GGT activity without a change in warfarin metabolism. When alterations in both plasma GGT activity and plasma warfarin concentration occurred together in response to drug administration the changes followed a similar time course, occurring after about one week of drug administration with maximal changes at about 10 or 15 days. Administration of chlordiazepoxide, diazepam, nitrazepam, and methaqualone did not stimulate the rate of warfarin metabolism in four patients studied, but plasma GGT activity increased significantly in two of these four instances. The implications of these observations in the interpretation of plasma GGT activities are discussed.

Acyltransferases↗
PubMed1972

Interactions of benzodiazepines with warfarin.

Administration of nitrazepam (10 mg nightly), diazepam (15 mg/day), and chlordiazepoxide (15 and 30 mg/day) had no effect on steady-state plasma warfarin concentrations, the plasma half-life of warfarin, or anticoagulant control in patients and it appears safe to prescribe these agents to patients on long-term oral anticoagulants. Urinary excretion of 6 beta-hydroxycortisol, however, increased in two out of five patients given chlordiazepoxide. In rats pretreatment with chlordiazepoxide (40 mg/kg for four days) caused stimulation of liver microsomal enzyme activity but neither diazepam nor nitrazepam had this effect.

Adult↗