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Studies were undertaken in 12 normal, male subjects to determine whether a metabolic interaction occurs between ketoconazole and mephenytoin. A single dose (400 mg) of ketoconazole produced a reduction in the 0-8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug and after 28 daily doses the median value was further reduced to 42.9% of its baseline value. Within 7 days following discontinuation of ketoconazole the enantiomeric ratio had returned to its pre-study value. These findings are consistent with ketoconazole being a potent in vivo inhibitor of mephenytoin's 4- hydroxylation and confirm the ability of such an interaction to be predicted by in vitro studies with human liver microsomes. By contrast, ketoconazole had a much smaller effect on the 0-8 h urinary metabolic ratio of debrisoquine, indicating that ketoconazole has a selective inhibitory effect on different forms of cytochrome P-450. [ABSTRACT FROM AUTHOR]

Antipyrine half-life has been determined from measurements of antipyrine concentrations in spontaneously voided urine specimens in eleven subjects, studied on a total of forty-seven different occasions while receiving no drugs, interferon or ketoconazole. Plasma and saliva half-lives show good intrasubject correlation. Plasma and urine half- lives show good intrasubject correlation provided total urine output is at least 1.1 l day-1. The range of intrasubject correlation coefficients for plasma and urinary half-lives was 0.76 to 0.98, with a median value of 0.85. Saliva and urine half-lives show good intrasubject correlation, with the range of intrasubject correlation coefficients from 0.74 to 0.98, and with a median value of 0.75. There is a small but consistent bias towards shorter urinary half-life estimates; this averaged 0.75 h for the plasma-urine studies and 0.192 h for the saliva-urine studies. There were parallel changes in antipyrine half-life estimated from plasma and urine for one of our subjects who received multiple doses of recombinant beta-interferon and had a 150% increase in antipyrine half-life over the study period. [ABSTRACT FROM AUTHOR]