Azole antifungals substrates

In the synthesis of 2,2,5-trisubstituted tetrahydrofurans, a novel class of orally active azole antifungal compounds, Saksena95 reported that the key step of Diels-Alder reaction in water led to the desired substrate virtually in quantitative yields (Eq. 12.34), while the same reaction in organic solvent resulted in a complicated mixture with only less than 10% of the desired product being isolated. This success made the target compounds readily accessible. 

Toxicity Nausea, diarrhea, thrombocytopenia, hyperbilirubinemia, and nephrolithiasis occur. To reduce renal damage, it is important to maintain good hydration. Indinavir is a substrate for and an inhibitor of the cytochrome P450 isoform CYP3A4 and is implicated in drug interactions. Serum levels of indinavir are increased by azole antifungals and decreased by rifamycins. Indinavir increases the serum levels of antihistamines, benzodiazepines, and rifampin. 

Fig. 40.4. Mechanism of azole/CYP450 binding. The basic nitrogen of azole antifungal agents forms a bond to the heme iron of CYP450 enzymes, preventing the enzyme from oxidizing its normal substrates. Ketoconazole is representative of the azole antifungals.

Information seems to be limited to these reports. Neither fluconazole nor ketoconazole normally appears to interact to a relevant extent in most patients. However, it seems that very occasionally some changes occur so bear this interaction in mind in the case of unexpected changes in theophylline levels, adverse effects or uncontrolled symptoms. Other azole antifungals such as itraconazole, posaconazole and voriconazole, which are substrates for and inhibitors of CYP2C19, CYP2C9, and/or CYP3A4, are also unlikely to interact with theophylline. 

The azole antifungal drug ketoconazole was found to inhibit Fe(III)-ascorbate dependent lipid peroxidation using either rat hver microsomes or ox-brain phospholipid hposomes as the substrates (Wiseman et al. 1991). It also inhibited microsomal peroxidation induced by the Fe(III)-ADP/NADPH system. The related azoles, miconazole and clotrimazole, were much weaker inhibitors than ketoconazole. Ketoconazole was approximately equipotent... 

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