Cytochrome P450-Activated Prodrugs: Targeted Drug Delivery

Abstract

Cytochrome P450 (CYP) enzymes are a superfamily of heme containing proteins that catalyze xenobiotic metabolism phase I reactions. Oxidation reactions are the most common CYP-catalyzed reactions for both endogenous substrates and exogenous compounds, including drugs, although CYP enzymes are capable also to catalyze reduction reactions. Whereas the majority of clinically used drugs are inactivated by CYPs, several prodrugs are bioconverted to their active species by these enzymes. Therefore, this mechanism could be exploited to a greater extend, e.g. by taking advantage of the different CYP enzymes to achieve targeted drug delivery, to improve efficacy or to decrease the unwanted adverse effects of existing and novel drug molecules. This review describes the potential of CYP enzymes in prodrug design and summarizes a wide variety of CYP-activated prodrug structures, which are on the market or under the development. The bioactivation mechanisms of each CYP-activated prodrug structure are described and the specificity for the different forms of CYP enzymes is discussed.

Characterisation of the oxysterol metabolising enzyme pathway in mismatch repair proficient and deficient colorectal cancer

“…There was no evidence of intra-tumour heterogeneity and this is consistent with our previous studies of other cytochrome P450 enzymes in tumours [29, 30, 31]. With some cytochrome P450s especially CYP1B1 showing increased expression in tumour cells and the tumour associated expression of individual cytochrome P450s has been exploited as therapeutic targets for P450 mediated pro-drug activation and as a cancer vaccine [29, 32–34]. The cytochrome P450s involved in the metabolism of a diverse range of endogenous compounds including eicosanoids, fatty acids, steroids and vitamins are the CYP4 family and higher numbered cytochrome P450 families.…”

Prodrugs—from Serendipity to Rational Design

“…The use of oxazaphosphorines can be associated with severe toxicity, because their metabolism leads to the formation of the highly reactive metabolite acrolein, which is responsible for urotoxicity, neurotoxicity, and nephrotoxicity (Huttunen et al, 2008;Giraud et al, 2010). CYP2B6 and CYP2C19 are highly polymorphic, such that some of their variant alleles have reduced or no activity compared with the wild-type allele.…”

“…The NADPH-dependent P450-catalyzed hydroxylation of the furan ring produces an intermediate that spontaneously decomposes to the active 5-FU and the succinic aldehyde moiety. CYP2A6 is the principal enzyme responsible for the activation of tegafur in human liver microsomes, but CYP1A2, CYP2C8, and thymidine phosphorylase also contribute to this process (Huttunen et al, 2008). Several clinical studies have indicated that systemic exposure to tegafur is increased in patients with CYP2A6 PM genotype, caused either by deletion of the CYP2A6 gene or the presence of inactive alleles, leading to reduced enzyme activity (Bai et al, 2010).…”

“…The CYP2D6 enzyme is responsible for the oxidation of the most abundant tamoxifen metabolite, N-desmethyltamoxifen, to endoxifen (Jordan, 2007;Huttunen et al, 2008;Sideras et al, 2010). Considerable mechanistic, pharmacologic, and clinical pharmacogenetic evidence supports the concept that CYP2D6 genetic variants and phenocopying effects through drug interactions with CYP2D6 inhibitors can influence plasma concentrations of active tamoxifen metabolites and negatively affect the therapeutic outcome.…”

Anticancer Drug Metabolism: Chemotherapy Resistance and New Therapeutic Approaches

“…Another example is 1,4-bis-([2-(dimethylamino-Noxide)ethyl]amino)5,8-dihydroxy anthracene-9,10-dione (AQ4N), a bioreductive prodrug that needs activation by CYP2S1 and CYP2W1 in tumor tissues to be converted to a topoisomerase II inhibitor (Nishida et al, 2010). Therefore, because CYPs are involved in either the bioactivation or the inactivation of both carcinogens and anticancer drugs (Huttunen et al, 2008), they play important roles in the etiology of cancer diseases and as determinants of cancer therapy (Oyama et al, 2004).…”