Ketoconazole bioavailability

PisciteUi SC, Goss TF, Wilton JH, D Andrea DT, Goldstein H, Schentag JJ. Effects of ranitidine and sucraltete on ketoconazole bioavailability. AnUmicrob Agents ChemoUter (1991) 35,1765-71. 

L. Z., Mekki, Q., Dressler, D. et al., Tacrolimus oral bioavailability doubles with coadministration of ketoconazole, Clin. Pharmacol. Ther. 1997, 62, 41-49. 

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. 

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. 

Proton pump inhibitors cause a profound and long-lasting inhibition of gastric acid secretion therefore, proton pump inhibitors may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole, ampicillin, iron salts, digoxin, cyanocobalamin). 

As a consequence of its high lipophilicity and low aqueous solubility, gastric acidity is also required for itraconazole absorption (Haria et al., 1996). It is best absorbed when administered with food, although there is considerable interpatient variabihty. The oral bioavailability or itraconazole from a 100-mg solution dose was 55%. Like ketoconazole, its bioavailability and half-life are dose-dependent, indicating saturable metabolism. Once absorbed, itraconazole is highly plasma protein bound (99.8%) and widely distributed (10.7 L/kg). Although itraconazole is widely metabolized, it does produce an active metabolite by hydroxylation of the triazolone side-chain. 

The original formulation, a buffered powder, has been replaced by chewable and dispersible buffered tablets with greater bioavailability (30-40%) a new enteric-coated formulation further improves patient convenience and tolerability. Since the chewable tablets contain both phenylalanine (36.5 mg) and sodium (1380 mg), caution should be exercised in patients with phenylketonuria and those taking sodium-restricted diets. Didanosine should be taken on an empty stomach and, because of the buffered formulation, should be administered at least 2 hours after administration of drugs requiring acidity for optimal absorption (eg, ketoconazole, itraconazole, dapsone). 

Table 3 Measures of Cyclosporin Bioavailability and Hepatic Extraction After Oral Administration in the Presence or Absence of the CYP3A Inhibitors Ketoconazole and Erythromycin and the CYP3A Inducer Rifampin...

Fleishaker JC, Pearson PG, Wienkers LC, et al. Biotransformation of tirilazad in humans 2. Effect of ketoconazole on tirilazad clearance and oral bioavailability. J Pharmacol Exp Ther 1996 277 991-998. 

The intrinsic kinetic properties of the victim drug also influence the potential clinical consequences of an interaction. For orally administered medications that undergo significant presystemic extraction, impairment of clearance by a CYP inhibitor may produce increases in bioavailability (reduced presystemic extraction) as a consequence of reduced clearance. The effects may be particularly dramatic for CYP3A substrates (such as triazolam, midazolam, or buspirone) that undergo both hepatic and enteric presystemic extraction. As an example, coadministration of the CYP3A inhibitor ketoconazole with triazolam produced very large increases in area under the plasma concentration-time curve... 

AUC) and increases in peak plasma concentration (Cmax) of triazolam (73,74) (Fig. 2). Cotreatment of ketoconazole with alprazolam, also a CYP3A substrate, produced a large increase in AUC for alprazolam (74). However, alprazolam is a low-extraction compound with bioavailability ordinarily in the range of 90% (75). As such, the reduction in alprazolam clearance caused by ketoconazole was evident mainly as prolonged elimination half-life but without a significant change in Cmax. 

Pharmacokinetics Itraconazole is well-absorbed orally and food increases its bioavailability. It is extensively bound to plasma proteins and distributes well throughout most tissues, including bone, sputum and adipose tissues. However, therapeutic concentrations are not attained in the CSF. Like ketoconazole it is extensively metabolized in the liver but does not inhibit androgen synthesis. Little of the parent drug appears in the urine and thus doses do not have to be reduced in renal failure. 

CARBAMAZEPINE ANTIFUNGALS - ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE, VORICONAZOLE 1 plasma concentrations of itraconazole and of its active metabolite, ketoconazole, posaconazole and voriconazole, with risk of therapeutic failure, t carbamazepine plasma concentrations These azoles are highly lipophilic, and clearance is heavily dependent upon metabolism by CYP isoenzymes. Carbamazepine is a powerful inducer of CYP3A4 and other CYP isoenzymes (CYP2C18/19, CYP1A2), and the result is very low or undetectable plasma levels. Inhibition of P-gp t bioavailability of carbamazepine Avoid co-administration of posaconazole or voriconazole with carbamazepine. Watch for inadequate therapeutic effects, and t dose of itraconazole. Higher doses of itraconazole may not overcome this interaction. Consider use of the less lipophilic fluconazole, which is less dependent on CYP metabolism. Necessary to monitor carbamazepine levels... 

AZOLES - FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CORTICOSTEROIDS t adrenal suppressive effects of corticosteroids, which may T risk of infections and produce an inadequate response to stress scenarios Due to inhibition of CYP3A4-mediated metabolism of corticosteroids and inhibition of P-gp (t bioavailability of corticosteroids) Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat... 

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