Deleterious effects of reactive metabolites

Abstract

A number of drugs have been withdrawn from the market or severely restricted in their use because of unexpected toxicities that become apparent only after the launch of new drug entities. Circumstantial evidence suggests that, in most cases, reactive metabolites are responsible for these unexpected toxicities. In this review, a general overview of the types of reactive metabolites and the consequences of their formation are presented. The current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these procedures will be discussed. Reasonable reasons for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development. This will, in turn, help us to design and bring safer drugs to the market.

Keywords: adverse drug reactions; drug design; metabolism; reactive metabolites.

Figure 1

The relationship between metabolism, activation, detoxication, and toxicity of a xenobiotic.

Figure 2

Free radical mechanism of cyclopropylamine ring opening: insights into trovafloxacin-induced hepatotoxicity.

Figure 3

Reactive oxygen species (rOS). O₂- superoxide radical, H₂O₂ = hydrogen peroxide, SOD = superoxide dismutase, Cat = catalase, NO = nitric oxide, NO₂-nitrite, ONOO⁻ = peroxynitrite, Nitrated proteins are biomarkers for oxidative stress. Red indicates disease promoting proteins or compounds; green, protective factors; arrows, reactions or transformations; a box indicates a protein for example, an enzyme or receptor. The processes shown within the grey area occur naturally in the body.

Figure 4

Metabolism of paracetamol and formation of reactive metabolites.

Figure 5

Proposed mechanisms of P450 inactivation and hepatotoxicity by components of kava extract.

Figure 6

Postulated bioactivation pathways which explain the mutagenicity of the anti-obesity agent 2-(3-chlorobenzyloxy)-6-(piperazin-1-yl)pyrazine (1) in the Salmonella Ames test.

Figure 7

Alkylation by and redox cycling of quinones.

Figure 8

Potential cyto- and genotoxic pathways triggered by myeloperoxidase- catalyzed generation of etoposide phenoxyl radicals. VP = etoposide, Ph = phenoxyl radicals, sQ = semi-quinone free radical, CA = chromosomal aberration, LP = lipid peroxidation, RSH = intracellular thiols, RS^· = thiyl radicals, RS-S-^·R = disulfide anion-radicals, HO^· = hydroxyl radical.

Figure 9

Bioactivation of the remoxipride metabolite, NCQ344, to a reactive p-quinone.

Figure 10

Bioactivation of lumaricoxib to a reactive p-iminoquinone.

Figure 11

Bioactivation of acolbifene to reactive p-quinonemethide and p-diquinonemethide metabolites.

Figure 12

Bioactivation of carbamazepine to a reactive carbamazepine-10, 11-epoxide intermediate.

Figure 13

Bioactivation of zomepirac to a reactive arene oxide intermediate.

Figure 14

Bioactivation of diclofenac to a reactive acyl glucuronide.

Figure 15

Bioactivation of the antifungal compound NDPS to a reactive O-sulfate.

Figure 16

Proposed pathways for biotransformation of [14C]BMS-204352 in humans.

Figure 17

Schematic illustration of the risk and benefits for drug development. See text for explanation.