Ketoconazole, effect

Imidazoles 1% (e.g.,ketoconazole) Effective against trophozoites but not cysts never used as primary therapy but may be used concurrently... 

KandrotasRJ, Slaughter RL, Brass C, Jusko WJ. Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol. Clin Pharmacol Ther (1987) 42,465-70. 

Ziircher RM, Frey BM, Frey FJ. Ketoconazole effects on corticosteroid disposition. Clin Pharmacol Ther( 990) 47,419-21. 

There is a decreased absorption of lansoprazole when it is administered with sucralfate Lansoprazole may decrease tiie effects of ketoconazole, iron salts, and digoxin. When lansoprazole is administered with theophylline, there is an... 

Oral administration of bicarbonate may decrease the absorption of ketoconazole. Increased blood levels of quinidine, flecainide, or sympatiiomimetics may occur when these agents are administered with bicarbonate There is an increased risk of crystalluria when bicarbonate is administered with the fluoroquinolones. Fbssible decreased effects of lithium, methotrexate, chlorpropamide, salicylates, and tetracyclines may occur when these drag s are administered with sodium bicarbonate. Sodium bicarbonate is not administered within 2 hours of enteric-coated drugs the protective enteric coating may disintegrate before the drug reaches the intestine. 

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. 

Treat nipple candidiasis by applying topical ketoconazole, nystatin, or miconazole to the nipples after each feeding and by administering oral nystatin drops to the breast-feeding infant12 (Table 44-5). In severe or recurrent cases, the mother may be treated with oral fluconazole.12,14 Although messy, gentian violet applied topically to both the nipples and the infant s mouth is also effective for resistant cases.12... 

Systemic adverse effects associated with vaginal azoles are less frequent than with oral products. Local discomfort such as burning may occur with the first application. Fifteen percent of patients experience gastrointestinal side effects with orally administered antifungal agents.13 Oral ketoconazole is associated with hepatic toxicity at a rate of 1 in 15,000.14... 

Two to three weeks of fluconazole or itraconazole solution are highly effective and demonstrate similar clinical response rates.32 Doses of 100 to 200 mg are effective in immunocompetent patients but doses up to 400 mg are recommended for immunocompromised patients. Due to variable absorption, ketoconazole and itraconazole capsules should be considered second-line therapy. In severe cases, oral azoles may prove ineffective, warranting the use of amphotericin B for 10 days. Although echinocandins and voriconazole are effective in treatment of esophageal candidiasis, experience remains limited. 

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 inhibits a variety of cytochrome P450 enzymes, including 11-hydroxylase and 17-hydroxylase. It is highly effective in lowering cortisol in Cushing s disease, and patients can be maintained successfully on therapy for months to years. The most common adverse effects are reversible elevation of hepatic transaminases and GI upset. It can cause gynecomastia and lower plasma testosterone values. 

Itraconazole and ketoconazole (200-800 mg/day orally for 1 year) are effective in 74% to 86% of cases, but relapses are common fluconazole 200-400 mg daily is less effective (64%) than ketoconazole or itraconazole, and relapses are seen in 29% of responders Severe disease Amphotericin B 0.7 mg/kg/day for a minimum total dose of 35 mj kg is effective in 59% to 100% of cases and should be used in patients who require hospitalization or are unable to take itraconazole because of drug interactions, allergies, failure to absorb drug or failure to improve clinically after a minimum of 12 weeks of itiaconazole therapy... 

Androgen synthesis inhibitors provide symptomatic, but brief, relief in approximately 50% of patients. Aminoglutethimide causes adverse effects in 50% of patients, such as lethargy, ataxia, dizziness, and self-limiting rash. The adverse effects of ketoconazole are GI intolerance, transient increases in liver and renal function tests, and hypoadrenalism. 

Triazolam is distributed quickly because of its high lipophilicity, and thus it has a short duration of effect. Erythromycin, nefazodone, fluvoxamine, and ketoconazole reduce the clearance of triazolam and increase plasma concentrations. 

Figure 2.8 Effective permeability coefficients (Peff) (xlO-6) of verapamil calculated from appearance in venous blood (P 00 ) and disappearance from lumen (Peff) in the presence and absence of PSC833, midazolam, or ketoconazole in the vascularly perfused intestinal.

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. 

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. 

Tannergren C, Knutson T, Knutson L and Lennernas H (2003) The Effect of Ketoconazole on the In Vivo Intestinal Permeability of Fexofenadine Using a Regional Perfusion Technique. BrJ Clin Pharmacol 55 pp 182-190. 

Salphati L and Benet LZ (1998) Effects of Ketoconazole on Digoxin Absorption and Disposition in Rat. Pharmacology 56 pp 308-313. 

Recent in vitro hybridization studies in the rat have demonstrated that t)rpical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the s)mthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid s)mthesis inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRT) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. 

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