This study was based on the clinical observation of a higher phenprocoumon requirement in these diabetic patients simultaneously treated with phenprocoumon (MarcoumarR) 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. In addition, DMB could inhibit the known enterohepatic circulation of phenprocoumon and so increase phenprocoumon elimination. Therefore, careful monitoring of the pharmacodynamic effect should be performed in those patients treated with a combination of phenprocoumon and DMB.

Most pharmaceuticals, toxic compounds, mutagens, and carcinogens undergo metabolism in the human body. Differences in drug metabolizing enzymes cause differences in susceptibility towards effects or side effects of these compounds. This chapter presents a comparison of epoxide hydratase (EH) activity in human individuals. Activities were measured in biopsy samples of liver, which is the main site of drug metabolism, and of lung, which is an organ that is continually exposed to potential enzyme inducers and to carcinogenic compounds. EH was studied in native lymphocytes, cultured lymphocytes, and fibroblasts in which environmental influences can be controlled and the genetic differences can be discriminated from environmental effects. The chapter explains that EH activity varies from organ to organ and, in some organs, from individual to individual. This is apparent in liver and lung, which are organs heavily exposed to foreign compounds. The much smaller variation in control liver and in cells in culture under uniform environmental conditions indicates that epigenetic factors are essential for the differences.

The effect of different doses of dimethylbiguanide (DMB) administered by the i.v. and i.d. route on liver blood flow, blood glucose and plasma immunoreactive insulin was investigated in anaesthetized rats. Liver blood flow was measured by thermocouples implanted into the liver utilising Grayson's principle of “internal calorimetry”. In addition blood glucose and immunoreactive insulin in the plasma was measured at different time intervals following the different doses of DMB. Intraarterial BP was monitored during the whole experiment. Following 100 mg/kg DMB i.v. a significant increase in liver blood flow, blood glucose, plasma immunoreactive insulin and BP was observed. 50 mg/kg DMB i.v. did not affect any of the parameters measured, while 150 mg/kg DMB was already a toxic dose. After i.d. administration no changes were seen following a dose of 175 mg/kg DMB and 1500 mg/kg DMB was already toxic. 500 mg/kg, however, showed a similar significant increase in liver blood flow, blood glucose, plasma immunoreactive insulin and BP was observed. 50 mg/kg effects observed could be suppressed by a simultaneous administration of 1 mg/kg propranolol i.v. In addition a decrease in liver blood flow occurred which is explained by a direct effect of the β-adrenergic blocking agent propranolol on the liver vasculature. Therefore a selective β-adrenergic effect of the biguanides seems a likely explanation for the increased liver blood flow following DMB administration.

Administration of therapeutic doses of the hypoglycemic drug dimethylbiguanide (metformin) for 10 days to rats failed to lead to increases in aminopyrine N-demethylase, benzo(a)pyrene hydroxylase and epoxide hydrase, activities representative for reactions catalyzed by drug metabolizing microsomal enzyme systems which can be induced by distinctly different groups of drugs. The concentration of cytochrome P-450, the end-oxidase of the microsomal mixed function oxidase(s) was not elevated and its spectral properties were unchanged. Therefore the need for higher doses of the anticoagulant drug phenprocoumon (Marcoumar) and the increase in overall elimination of this drug after treatment of patients with dimethylbiguanide appears not to be due to an induction of drug metabolizing enzymes but rather to the observed increase in liver blood flow.