Defining Targets for Investigating the Pharmacogenomics of Adverse Drug Reactions to Antifungal Agents

Abstract

Adverse drug reactions (ADRs) associated with antifungal therapy are major problems in patients with invasive fungal infections. Whether by clinical history or patterns of genetic variation, the identification of patients at risk for ADRs should result in improved outcomes while minimizing deleterious side effects. A major contributing factor to ADRs with antifungal agents relates to drug distribution, metabolism and excretion. Genetic variation in key genes can alter the structure and expression of genes and gene products (e.g., proteins). Thus far, the effort has focused on identifying polymorphisms with either empirical or predicted in silico functional consequences; the best candidate genes encode phase I and II drug-metabolizing enzymes (e.g., CYP2C19 and N-acetyltransferase), plasma proteins (albumin and lipoproteins) and drug transporters (P-glycoprotein and multidrug resistance proteins), which can affect the disposition of antifungal agents, eventually leading to dose-dependent (type A) toxicity. Less is known regarding the key genes that interact with antifungal agents, resulting in idiosyncratic (type B) ADRs. The possible role of certain gene products and genetic polymorphisms in the toxicities of antifungal agents are discussed in this review. The preliminary data address the following: low-density lipoproteins and cholesteryl ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related ADRs; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing monooxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; CYP enzymes and P-glycoprotein in drug interactions between azoles and coadministered medications; multidrug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity; and mast cell activation in caspofungin histamine release. This will focus on high-priority candidate genes, which could provide a starting point for molecular studies to elucidate the potential mechanisms for understanding toxicity associated with antifungal drugs as well as identifying candidate genes for large population prospective genetic association studies.

Immunomodulatory effects of antimicrobial agents. Part II: antiparasitic and antifungal agents

“…Data from [68,69]. Review 8 and 9 are involved in 5-flucytosine bone-marrow toxicity and mast cell activation in caspofungin-induced histamine release [85].…”

Pharmacotherapy of Invasive Fungal Infections with Voriconazole

“…The mechanism underlying these dermatologic adverse events remains unknown. 76,77 Although most commonly the rash is restricted to facial erythema in sun-exposed areas, more serious eruptions can occur necessitating discontinuation of the drug. 78 Pseudoporphyria, toxic epidermal necrolysis, and multifocal facial squamous cell carcinomas have also been reported.…”

“…58,85,[87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] Triazoles have numerous clinically significant drug interactions, the list is constantly expanding and the majority of those currently identified are presented in Table 2 17,85,86,[91][92][93][94][95][96][97][98][99][100][101][102] and Table 3. [52][53][54][55]57,62,[75][76][77][78][79][80][81][82]86 Most of these interactions arise from competitive inhibition of liver oxidative metabolism via rapid reversible binding to …”

Differential internalization of amphotericin B – Conjugated nanoparticles in human cells and the expression of heat shock protein 70

“…However, it is unclear whether the toxicity effect is mediated by an interaction of AmB with cell membrane or requires the intracellular delivery of AmB. Further, although several experimental results indicate that the toxicity of AmB is due to its ability to induce oxidative stress and disturb normal ion functioning [2,10,11], it is unclear whether both mechanisms occur at the same time or are dependent on the concentrations of AmB.…”