Desacetyl-Diltiazem Displays Severalfold Higher Affinity to CYP2D6 Compared with CYP3A4

Abstract

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:It has earlier been shown that the isoenzymes CYP2D6 and CYP3A4 are involved in O-and N-demethylation of diltiazem (DTZ), respectively. Apparently, CYP3A4 plays a more prominent role than CYP2D6 in the overall metabolism of DTZ. However, previous observations indicate that the opposite might be true for the pharmacologically active metabolite desacetyl-DTZ (M1). Thus, the aim of the present in vitro investigation was to study the relative affinity of M1 to CYP2D6 and CYP3A4. Immortalized human liver epithelial cells transfected with either CYP2D6 or CYP3A4 were used as a model system, and the presence of M1 and its metabolites in the cell culture medium was analyzed by high-performance liquid chromatography/UV detection both before and following 90 min of incubation. The estimated K m value for the CYP2D6-mediated Odemethylation of M1 was approximately 5 M. In comparison, the affinity of M1 to CYP3A4 (N-demethylation) was about 100 times lower (K m , Ϸ540 M) than to CYP2D6. These in vitro data suggest that M1 metabolism via CYP2D6, in contrast to the parent drug, probably is the preferred pathway in vivo. Metabolism mediated through CYP2D6 is associated with a substantial interindividual variability, and since M1 expresses pharmacological activity, individual CYP2D6 metabolic capacity might be an aspect to consider when using DTZ.

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“…It was reported that diltiazem is metabolized by CYP3A4 both in the liver and small intestine [40,41] . The absorption of diltiazem in the intestinal mucosa was inhibited by P-glycoprotein efflux pump [42,43] .…”

Use of Human Plasma Samples to Identify Circulating Drug Metabolites that Inhibit Cytochrome P450 Enzymes

“…Diltiazem and desmethyldiltiazem were shown to be CYP3A4 inhibitors using the approach, as expected (albeit baseline chromatographic resolution was not attainable for these two compounds). Importantly, desacetyldiltiazem was identified as a CYP2D6 inhibitor using this approach, which was reported previously (Molden et al, 2002). If this approach were used prospectively, it would have directed a closer examination of desacetyldiltiazem as a possible CYP2D6 inhibitor.…”

“…This offers an example of a metabolite possessing P450 inhibition activity although the parent drug does not. Desacetyldiltiazem was previously reported to inhibit CYP2D6 and a small dmd.aspetjournals.org DDI has been reported for diltiazem and metoprolol, a CYP2D6 substrate (Tateishi et al, 1989;Molden et al, 2002). No inhibition peaks were observed in activity-grams for the other enzymes (data not shown).…”

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“…The phosphorodiamidate morpholino oligomer chemistries have been reported in the literature elsewhere [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. A PMO, etiplersen, is currently under evaluation in clinical trials for the treatment of Duchenne Muscular Dystrophy [29,30].…”

“…Most importantly, compared to conventional antisense approaches, PMOs are highly resistant to degradation [14]. PMO compounds have demonstrated reliable and effective inhibition of gene expression including c-myc [15,16,17,18,19,20], cytochrome P4503A [21,22], and viruses including vesiviruses [23,24] and Ebola virus [25]. The PMO duplex with RNA is not a substrate for RNAseH [26] and as such they can be used to induce exon skipping in genes including dystrophin [27,28] for the treatment of patients with Duchenne Muscular Dystrophy [29,30].…”