phenprocoumon and Diabetes-Mellitus

This study was based on the clinical observation of a higher phenprocoumon requirement in these diabetic patients simultaneously treated with phenprocoumon (Marcoumar) and dimethylbiguanide (DMB), and of a drug interaction observed in a patient. These higher requirements of phenprocoumon, suggesting an increased elimination, could have been due to an enhancement of liver microsomal enzyme activity and/or an increase in liver blood flow. Various studies were performed to test this hypothesis. The clinically suggested higher phenprocoumon requirement was proven by a drug observation study. Hence a higher tablet consumption of phenprocoumon and a diminished anticoagulatory effect was found after treatment with DMB in doses of between 1 and 3 g. An increased elimination of phenprocoumon following DMB administration was also found in a pharmacokinetic study. The activity of the liver microsomal enzyme system, investigated in animal and man, showed no changes in the liver microsomal enzymes in animal studies or the in vivo parameters of liver microsomal enzyme activity in patients. Measuring liver blood flow in dogs, utilizing the indocyanine green clearance method, an increased flow of about 33% was observed. As changes in liver blood flow can increase the metabolism of some highly lipid soluble drugs, the increased metabolism of phenprocoumon during DMB treatment could be related to the increase in liver blood flow and not to changes in liver microsomal enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Hydroxycoumarins; Animals; Diabetes Mellitus; Dogs; Drug Interactions; Humans; Liver; Male; Metformin; Microsomes, Liver; Phenprocoumon; Rats; Rats, Inbred Strains; Regional Blood Flow

Tolbutamide belongs to those drugs responsible for the majority of drug interactions. E.g. Tolbutamide metabolism has been shown to be inhibited by coumarole derivatives. We determined plasma-tolbutamide levels in diabetic out-patients for one year. The results obtained indicate no difference in patients additionally treated with either digoxin or digoxin and alpha-methyldopa, or buformin and phenprocumone as compared with control groups. Interactions with respect to biotransformation should not be expected as far as digoxin, alpha-Methyldopa, or buformine were concerned, since these compounds do not share a common metabolic pathway with tolbutamide. In a different group of patients the elimination half life of tolbutamide under the influence of phenprocoumone was additonally determined. Differences could not be detected. This finding can be explained by means of enzyme-kinetic considerations, since phenprocumone, in contrast to dicoumarole, becomes metabolized according to a first order reaction. Competitive enzyme inhibition with tolbutamide which is metabolized similarly to phenprocoumone, therefore appears improbable.

Topics: Buformin; Diabetes Mellitus; Digoxin; Drug Interactions; Enzyme Inhibitors; Half-Life; Humans; Methyldopa; Phenprocoumon; Tolbutamide