Lis Skovsted

Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man.

Diphenylhydantoin half‐life was determined in 5 patients before and during treatment with carbamazepine. It caused a significant decrease in the diphenylhydantoin half‐life from 10.6 hours to 6.4 hours. Seven patients who for a period had been given diphenylhydantoin were also started on carbamazepine. This resulted in a fall in serum diphenylhydantoin levels in 3 of the patients. Alterations in warfarin half‐life, serum warfarin, and plasma prothrombin‐proconvertin concentration during carbamazepine treatment were compatible with a stimulation of warfarin metabolism. The effect of carbamazepine on diphenylhydantoin and warfarin metabolism is probably explained by an induction of the drug‐metabolizing enzyme system in the liver.

Disposition of Antipyrine and Phenytoin Correlated with Age and Liver Volume in Man

SummaryThe half-life and metabolic clearance rale (MCR) of antipyrine and phenytoin were determined in 14 young [mean age: 28.8 ± 8.3 (SD) years] and in 14 elderly [mean age: 83.5 ±7.1 (SD) years] subjects and correlated with liver volume, which was determined by ultrasonic scanning, to see if an age-dependent difference in drug metabolism could be explained by a reduced liver weight with age.The size of the liver was smaller in the elderly subjects even when related to decreased body surface. A significant decrease in serum albumin in the elderly compared with the younger group was also noted. The half-life of antipyrine was significantly longer in the elderly than in the younger group, 756 ± 318 and 465 ± 110 minutes, respectively, and the MCR was correspondingly lower in the elderly even when calculated per litre of liver volume, 22.8 ± 7.8 and 36.3 ± 8.9ml/minute/L liver volume, respectively. No significant differences in the 2 age groups were found in half-life and total clearance of phenytoin, but a reduced free phenytoin clearance was demonstrated in the elderly (240 ± 92ml/minute/L liver volume) compared with the younger (325 ± 81 ml/minute/L liver volume) group. No significant correlation was found between liver volume and the half-life of antipyrine and phenytoin. However, a significant correlation was demonstrated between liver volume and MCR of antipyrine as well as between total and free clearance of phenytoin. No correlation was found between the half-lives of the 2 drugs, while a significant correlation existed between the clearance values.It is suggested that the age-dependent reduction in drug clearance is due not only to a smaller liver volume, but is also a result of a reduced capacity of the liver microsomes per unit of liver in the elderly. With regard to age-dependent changes in drug metabolism, the protein binding of the actual drug has to be taken into consideration.

Sulfamethizole‐induced inhibition of diphenylhydantoin, tolbutamide, and warfarin metabolism

The influence of sulfamethizole on the metabolism of diphenylhydantoin (DPH), tolbutamide, and warfarin is examined. In 8 patients DPH mean half‐life (T/2) increased from 11.8 ± 3.3 hr to 19.6 ± 5.2 hr and mean metabolic clearance rate (MCR) decreasedfram 43.7 ± 16.8 to 28.1 ± 9.1 ml/min during sulfamethizole treatment. In 6 patients mean tolbutamide T/2 increased from 5.7 ± 1.2 to 9.2 ± 1.2 hr MCR decreased from 17.0 ± 5.4 to 10.5 ± 1.2 ml/min. In 2 patients warfarin T/2 increased from an average of 64.7 to 92.7 hr and MCR decreased from 1.65 ml/min to 1.05 ml/min. In 4 patients on long‐term DPH treatment after 1 wk on sulfamethizole, there was an increase in serum DPH concentration in 3. It is suggested that sulfamethizole inhibits hepatic metabolism of DPH, tolbutamide, and warfarin.