In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates.

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Davis JA, Rock DA, Wienkers LC, Pearson JT

In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates.

Drug Metab Dispos. 2012 Oct;40(10):1927-34. doi: 10.1124/dmd.112.046169. Epub 2012 Jun 29.

PubMed ID

22752008 [ View in PubMed

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Abstract

The in vitro characterization of the inhibition potential of four representative maytansinoid species observed upon hepatic and/or tumor in vivo processing of antibody-maytansine conjugates (AMCs) with cleavable and noncleavable linkers is reported. We investigated the free maytansinoid species N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), (S)-methyl-DM1, and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) as representative cleavable linker catabolites and Lysine-N(epsilon)-N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate-DM1 (Lys-MCC-DM1) as the representative noncleavable linker catabolite. Studies with recombinant human cytochromes P450 (P450s) indicate CYP2D6, CYP3A4, and CYP3A5 are the primary isoforms responsible for the oxidative metabolism of DM1, (S)-methyl-DM1, and DM4. Lys-MCC-DM1 was not metabolized by any of the P450 isoforms studied. DM1 was shown to be a reversible inhibitor of CYP2C8 (K(i) = 11 +/- 3 muM) and CYP2D6 (K(i) = 14 +/- 2 muM). Lys-MCC-DM1 and (S)-methyl-DM1 showed no reversible or time-dependent inactivation of any of the P450s studied. DM1 and DM4 inactivated CYP3A from human liver microsomes with K(i)/k(inact) values of 4.8 +/- 0.9 muM/0.035 +/- 0.002 min(-1) and 3.3 +/- 0.2 muM/0.114 +/- 0.002 min(-1), respectively. DM1 and DM4 inactivated recombinant CYP3A4 with K(i)/k(inact) values of 3.4 +/- 1.0 muM/0.058 +/- 0.005 min(-1) and 1.4 +/- 0.3 muM/0.117 +/- 0.006 min(-1), respectively. Because of instability in plasma, further characterization of the DM1 and DM4 intramolecular and intermolecular disulfide conjugates observed in vivo is required before an accurate drug-drug interaction (DDI) prediction can be made. AMCs with noncleavable thioether-linked DM1 as the cytotoxic agent are predicted to have no potential for a DDI with any of the major human P450s studied.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Mirvetuximab soravtansine	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inhibitor	Details