Ketoconazole metabolism

Because ketoconazole interferes with steroid synthesis and vitamin D metabolism, ketoconazole should not be used in children. It is not approved for use in children and there is no pediatric dosage range based on pharmacokinetic information in this population. 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

Theoretically buprenorphine metabolism could be inhibited by itraconazole, ketoconazole, grapefruit juice, and erythromycin or any other CYP3A4 inhibitor the effects may be greater than expected for the dose of buprenorphine being given may need to decrease buprenorphine dose. 

Fig. 7.16. Ketoconazole had no effect on human effective in vivo permeability (Pefr) of R/S-verapamil, antipyrine, and D-glucose. The data suggest that extensive intracellular metabolism (in the enterocyte mediated by CYP 3A4) of substrates such as R/S-verapamil...

Lennernas, H., The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans, Br. J. Clin. Pharmacol. 1999, 48, 180-189. 

Zhang, Y., Hsieh, Y., Izumi, T., Lin, E. T., Benet, L. Z., EfFects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats, J. Pharmacol. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

Primary adrenal insufficiency (Addison s disease) most often involves the destruction of all regions of the adrenal cortex. There are deficiencies of cortisol, aldosterone, and the various androgens. Medications that inhibit cortisol synthesis (e.g., ketoconazole) or accelerate cortisol metabolism (e.g., phenytoin, rifampin, phenobarbital) can also cause primary adrenal insufficiency. 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

Ketoconazole Efflux pump modulator and/or CYP inhibitor Can be used to demonstrate the impact of intestinally mediated efflux/metabolism on permeability estimates [114]. 

Sandstrom R, Knutson TW, Knutson L, Jansson B and Lennernas H (1999) The Effect of Ketoconazole on the Jejunal Permeability and CYP3A Metabolism of (R/S)-Verapamil in Humans. Br J Clin Pharmacol 48 pp 180-189. 

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

Concurrent use with ketoconazole, itraconazole, and nefazodone, medications that significantly impair the oxidative metabolism of triazolam mediated by cytochrome P-450 3A (CYP3A). 

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