Human pharmacogenomic models for antifungal efficacy and toxicity

Walsh T.J., Meletiadis J.

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Recent advances in the field of pharmacogenomics have elucidated the potential impact of heritable traits on the pharmacology and toxicology of antifungal agents. Candidate genes with potential phannacogenomic importance include those encoding proteins involved in [1] drug transport (absorption and excretion), [2] metabolism (phase I enzymes, such as cytochrome P450-dependent mixed-function oxidases, and phase II enzymes, such as glucuronosyltransferases), and [3] distribution of antifungal compounds, such as albumin, A1-acid glycoprotein, and lipoproteins. Phannacogenomic models for genetic variations in antifungal pharmacokinetics can be developed by using the tools of population genetics to define inter-individual differences in drug absorption, distribution, metabolism, and excretion. Variations in drug distribution, metabolism and excretion also may contribute to adverse drug reactions of antifungal agents. Genetic variations in critical target genes may alter the structure and expression of genes encoding phase I and II drug-metabolizing enzymes, such as CYP2C19 and N-acetyltransferase and drug transporters, such as P-glycoprotein and multidrug resistance proteins, may affect the disposition of antifungal agents and leading to dose-dependent (type A) toxicity. Genes encoding different lipoproteins may also affect the distribution of antifungal compounds. Considerably less is known about the possible role of genetic polymorphisms and gene products in contributing to idiosyncratic (type B or non-dose-dependent) toxicities of antifungal agents. There are several possible candidate genes that may affect antifungal agents: low- density lipoproteins and cholesterol ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related adverse drug reactions; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing mono oxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; and multi drug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity. Pharmacogenomic factors may become especially important in the treatment of immunocompromised patients or those with persistent or refractory mycoses that cannot be explained by elevated MICs and where rational dosage optimization of the antifungal agent may be particularly critical. Pharmacogenomics has the potential to shift the paradigm of therapy and to improve the selection of antifungal compounds through adjustment of dosages based upon individual variations in drug disposition.

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17th International Society for Human and Animal Mycology
    • ISHAM 17th (2009)