Tamoxifen oxidative metabolism

Tamoxifen can undergo several routes of oxidative metabolism (Fig. 7.9). Thus, as expected aromatic hydroxylation to yield, the 4-hydroxy tamoxifen is catalyzed by cytochrome P-450. This metabolite is eliminated after conjugation. Alternatively, oxidation of the alkyl groups attached to the nitrogen atom, also catalyzed by cytochrome P-450, leads to dealkylation (Fig. 7.9). These are detoxication pathways. 

Acolbifene is also metabolized to a QM (Scheme 10.10)64 formed by oxidation at the C-17 methyl group. This QM is considerably more reactive compared to the tamoxifen quinone methide, which indicates that the acolbifene quinone methide is an electrophile of intermediate stability (Table 10.2). In addition, the acolbifene QM was determined to react with deoxynucleosides, with one of the major adducts resulting from reaction with the exocyclic amino group of adenine.64... 

In addition, other drugs such as alosetron (2), cyproheptadine (12), diazepam (13) or tamoxifen (49) are AT-demethylated by various microorganisms as a major metabolic route. The carboxylic acid resulting from the oxidative cleavage of the piperidine ring of phencyclidine (36), probably proceeding through an... 

Fig. 2 Principal tamoxifen metabolic pathways of clinical interest. Abbreviations Tam (Tamoxifen), A -D- iam (A-desmethyl-tamoxifen), (V-DD-Tam (/V,(V-didesmethyl-tamoxifen), 4-OH-Tam (4-Hydroxy-Tamoxifen), 4 -OH-Tam (4 -Hydroxy-tamoxifen), Tam-NO (Tamoxifen-lV-oxide), Endoxifen (4-Hydroxy-A-desmethyl-tamoxifen), 4 -OH-iV-D-Tam (4 -Hydroxy-(V-desmethyl-tamoxifen), Tam-A -Gluc (Tamoxifen-A -glucuronide), Tam-4-O-Gluc (Tamoxifen-4-O-glucuronide), A-D-Tam-4-O-Gluc (iV-desmethyl-tamoxifen-4-O-glucuronide), Tam-4-0-S03H (Tamoxifen-4-O-sulfate), A-D-Tam-4-0-S03H (iV-desmethyl-tamoxifen-4-O-sulfate)...

The glucuronide metabolite of AZT was isolated from rat and human liver microsomal incubations (177), and the formation of a toxic metabolite of AZT was demonstrated in rat hepatocytes and liver microsomes (177). The metabolism of tamoxifen was examined in human liver homogenate and human Hep G2 cell line preparations by LC/API/MS (178). Several metabolites were detected in the human liver homogenate extracts, namely, N-didesmethyltamoxifen, a-hydroxy-tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, and tamoxifen N-oxide. All of these metabolites, except the N-didesmethyltamoxifen, were observed in the samples after incubating tamoxifen with the human Hep G2 cell line. In-vitro studies have also used MS to examine potential drug-drug interactions. For example, (179) demonstrated that the a2-agonist, dexmedetomidine, inhibited metabolism of the anesthetic alfentanil, whereas clonidine had no effect. 

It has been shown that tamoxifen and hydroxytamoxifen metabolize to 3,4-dihydroxytamoxifen [126]. This catechol can be oxidized by enzymes into ortho-quinone, which can react with DNA and proteins. A number of ferrocenyl catchols have been synthesized [127] (Fig. 42.9). 

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