The influence of dimethylbiguanide on phenprocoumon elimination and its mode of action. A drug interaction study.
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)
D015110:4-Hydroxycoumarins / Q000378:metabolism*; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000098:blood supply; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000201:enzymology; D010644:Phenprocoumon / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow
D015110:4-Hydroxycoumarins; D008687:Metformin; D010644:Phenprocoumon