Abstract
Phenformin (N[1]-phenethylbiguanide) is an oral hypoglycaemic agent which has been in use in the U. K. since 1959 for the treatment of some forms of diabetes. In recent years there have been reports of lactic acidosis associated with phenformin therapy, particularly in patients with renal or hepatic diseases. Metabolic and pharmacological studies in the rat and guinea-pig have shown that a number of factors are involved in the differences in response to phenformin in these species. Following a low oral dose of [2'-[14]C] phenformin rats excreted the radioactivity more rapidly than guinea-pigs and metabolised the drug more extensively. The rat eliminated almost 88% of a 7 mg/kg dose in the urine and faeces in 24h and the urine contained almost entirely 4-hydroxyphenformin (free and conjugated with glucuronic acid) which had no effects on blood lactate or glucose concentrations in this species. The guinea-pig excreted only 57% of a 25 mg/kg dose and 50$ of the urinary radioactivity (18.5% of the dose) was unchanged phenformin. The rat actively eliminated a large proportion (26% in 6h) of a 20 mg/kg intraduodenal dose of [2'-[14]C] phenformin in the bile, most of the radioactivity being attributable to the parent compound. In the guinea-pig biliary excretion was initially rapid but declined so that only 6% of the same dose was eliminated in 6h. The possibility that active biliary excretion of phenformin is inhibited by the pharmacological effects of the drug in the guinea-pig is discussed. After oral administration of [2'-[14]C] phenformin guinea-pig urine contained no 4-hydroxyphenformin but small amounts were detected after intraperitoneal administration. After both routes of administration guinea-pig urine contained a novel metabolite and its glucuronide. After oral administration a second novel metabolite was detected in guinea-pig faeces. These metabolites have not been completely characterised but in both cases the biguanide portion of the metabolites had been modified. The urinary metabolite is probably the product of aliphatic hydroxylation rather than aromatic hydroxylation. The identification and pharmacological properties of these metabolites remain to be determined. Preliminary in vitro studies using isolated rat and guinea-pig hepatocytes showed a faster rate of metabolism of [2'-[14]C]phenformin in rat cells. Rat cells produced significant amounts of 4-hydroxy-phenformin and its glucuronide but guinea-pig cells did not. In the rat the time taken to eliminate the dose and the extent to which phenformin was excreted unchanged in the urine increased with larger doses of the drug. After a high oral dose (100 mg/kg) 24% of the urinary radioactivity (12.5% of the dose) was attributable to unchanged phenformin. Pharmacological studies showed that the rise in blood lactate concentrations and fall in blood glucose concentrations associated with phenformin were dose related in the rat. The relationship between this observation and the increased elimination of unchanged drug in rat urine after high doses is discussed in terms of a first-pass effect for phenformin in the rat. The dose-response data indicated a critical dose in rats in the region of 120 mg/kg intraperitoneally, at which point marked increases in the pharmacological effects of the drug were seen. Normal and fasted guinea-pigs were more susceptible than rats to both pharmacological actions of phenformin. 4-Hydroxy-phenformin produced hyperlactataemia in guinea-pigs without affecting blood glucose levels. The possibility that the guinea-pig may produce a biologically active metabolite has not been resolved, but the differences in pharmacological response to phenformin in the rat and guinea-pig have been explained by the results in the thesis, which show a slower rate of metabolism and excretion of the drug in the guinea-pig, together with the established biochemical differences in the mechanisms of carbohydrate regulation in these species. Sodium dichloroacetate was effective in reducing phenformin-associated hyperlactataemia in rat and guinea-pig and prevented the increase in blood lactate levels caused by 4-hydroxyphenformin in guinea-pigs.