Effects of oral ketoconazole on renal function in healthy volunteers

Background Ketoconazole, an agent used to inhibit the P450 3A4 system in drug interaction studies, is not known to affect renal function. We were able to closely monitor the effects of ketoconazole on serum creatinine concentration (S[Cr]) in the course of a drug interaction study. Methods During a drug-drug interaction study 28 healthy males aged 20 to 60 years received 200 mg of ketoconazole alone every 12 hours for 3 days. S[Cr] was measured at screening, prior to and 36 and 72 hours after the first dose of ketoconazole. Results S[Cr] rose from 98± 3 uMols per L (Mean+ SEM) predose to 117± 4 uMols per L (p<0.001) 36 hours post ketoconazole intiation and remained elevated at 108± 3 uMols per L (p<0.05) after 72 hours on ketoconazole. The increase occurred in 23 out of 27 subjects. Blood urea nitrogen concentration (BUN) corrected for between subject variability increased 2± 1 mg/dl (p<0.025) 36 hours after the initial dose of ketoconazole. Conclusions Ketoconazole induces small but consistent increases in S[Cr]. The associated BUN elevation suggests a true decrease in glomerular filtration rate, rather than interference with S[Cr] assay or blocking tubular creatinine secretion. It is uncertain whether the observed renal effect of ketoconazole is mediated directly or indirectly, e.g., via its known actions on steroid synthesis. This effect of ketoconazole must be taken into consideration during drug interaction studies to prevent confounding effects of an investigational product on renal function. Clinical Pharmacology & Therapeutics (2005) 77, P81–P81; doi: 10.1016/j.clpt.2004.12.202