Synthesis and aromatase inhibition by potential metabolites of exemestane (6-methylenandrosta-1,4-diene-3,17-dione)

Buzzetti, Franco; Salle, E. Di; Longo, Antonio; Briatico, G.

doi:10.1016/0039-128x(93)90029-m

Cited by 35 publications

(32 citation statements)

References 11 publications

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“…In fact, Corona et al (2009) have recently shown that 17-hydroexemestane exhibits similar LC-MS/MS characteristics (m/z 299.1-Ͼ134.9). Another group of investigators showed that 6-hydroxymethylandrosta-1,4,6-triene-3,7-dione (6-hydroxymethylexemestane) is a potential metabolite of exemestane (Buzzetti et al, 1993). Therefore, these data are consistent with the suggestion that exemestane undergoes reduction of the 17-keto group and oxidation of the methylene group in position 6.…”

Section: Discussionsupporting

confidence: 64%

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

2010

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ABSTRACT:Exemestane is a potent and irreversible steroidal aromatase inhibitor drug used for the treatment of estrogen receptor-positive breast cancer. Our aim was to identify and assess the contribution of the specific cytochromes P450 (P450s) responsible for exemestane primary in vitro metabolism. With the use of high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques, 17-hydroexemestane (MI) formation and 6-hydroxymethylexemestane (MII) formation were found to be the predominant exemestane metabolic pathways. In a bank of 15 well characterized human liver microsomes with known P450 isoform-specific activities, the MI formation rate correlated significantly with CYP1A2 (Spearman r ‫؍‬ 0.60, p ‫؍‬ 0.02) and CYP4A11 (Spearman r ‫؍‬ 0.67, p ‫؍‬ 0.01) isoform-specific activities, whereas the MII production rate significantly correlated with CYP2B6 (Spearman r ‫؍‬ 0.57, p ‫؍‬ 0.03) and CYP3A (Spearman r ‫؍‬ 0.76, p ‫؍‬ 0.005) isoform-specific activities. Recombinant CYP1A1 metabolized exemestane to MI with a catalytic efficiency (Cl int ) of 150 nl/pmol P450 ؋ min that was at least 3.5-fold higher than those of other P450s investigated. Recombinant CYP3A4 catalyzed MII formation from exemestane with a catalytic efficiency of 840 nl/ pmol P450 ؋ min that was at least 4-fold higher than those of other P450s investigated. Among a panel of 10 chemical inhibitors tested, only ketoconazole and troleandomycin (CYP3A-specific chemical inhibitors) significantly inhibited the formation of MII by 45 and 95%, respectively. None of them markedly inhibited the formation of MI. In summary, exemestane seems to be metabolized to MI by multiple P450s that include CYP4A11 and CYP1A1/2, whereas its oxidation to MII is primarily mediated by CYP3A.

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Section: Discussionsupporting

confidence: 64%

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

2010

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“…One early study predicted that EXE, like many steroids, is vulnerable to phase I metabolism at the carbonyl group occupying this position [34]. Carbonyl-reducing enzymes catalyze similar reactions despite contributions from two distinct protein phylogenies, the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies [35].…”

Section: Introductionmentioning

confidence: 99%

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

Platt

Xia

Liu

et al. 2016

Pharmacogenetics and Genomics

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Objective Exemestane is a potent third-generation aromatase inhibitor used as endocrine therapy in breast cancer treatment and prevention. Characterization of its metabolic pathway is incomplete with ambiguity existing in the identity of enzymes driving production of its key metabolite, 17β-dihydroexemestane. The impact of genetic variation on exemestane metabolism is also unknown. This study seeks to describe cytosolic reductase involvement in hepatic exemestane metabolism and to assess the impact of functional polymorphisms on metabolite production. Methods Phase I metabolites were identified in incubations of exemestane with pooled human liver cytosol or recombinant protein for AKR1Cs and CBR1. Kinetic parameters characterizing exemestane reduction were measured for purified wildtype enzymes, and nonsynonymous variants occurring at >1% minor allele frequency using UPLC/MS/MS. Results Human liver cytosol, CBR1, AKR1C1, AKR1C2, AKR1C3, and AKR1C4 reduce exemestane to active primary metabolite 17β-dihydroexemestane. Formation of a novel metabolite, 17α-dihydroexemestane, was catalyzed by recombinant AKR1C4 and CBR1 in addition to hepatic cytosol. Variants AKR1C3 Arg258Cys and AKR1C4 Gly135Glu had significantly decreased affinity for EXE relative to their respective wildtypes. Five common AKR1C3 polymorphisms were associated with decreased rates of catalysis while AKR1C4 Gly135Glu increased the velocity of EXE reduction. Conclusions AKR1Cs and CBR1 catalyze exemestane reduction in vitro. These results imply that cytosolic ketosteroid reductases may participate in the exemestane metabolic pathway in vivo. In addition, several common variants were associated with altered enzymatic activity, suggesting that functional polymorphisms could play an important role in overall exemestane metabolism and activity by altering the extent and duration of 17β-dihydroexemestane exposure.

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“…Polymorphisms in genes that code for drug-metabolizing enzymes may contribute to this variation. As described previously, glucuronidation of the AIs occurs via the uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), an enzyme that plays a major role in the deactivation and clearance of anastrozole and exemestane specifically [8]. In a preliminary report using human liver microsomes, Lazarus et al [30] noted that a homozygous UGT2B17 deletion (*2/*2) genotype was associated with a 14-fold decrease in glucuronidation activity of 17-dihydroexemestane, a major active metabolite of exemestane, compared with individuals with the wildtype gene (P<0.001).…”

Section: Genetic Polymorphisms Impacting Ai Metabolismmentioning

confidence: 98%

“…It is believed, however, that phase 1 metabolism of these agents occurs predominantly by CYP3A-mediated oxidation or by reduction [7]. Phase 2 metabolism, or glucuronidation, subsequently occurs via the hepatic uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) and plays a major role in the deactivation and clearance of these agents [8]. Ongoing studies investigate differences in metabolism of specific agents that can guide future pharmacogenetic research.…”

Section: Aromatase Inhibitors: Pharmacology and Clinical Applicationmentioning

confidence: 99%

Pharmacogenetics of Aromatase Inhibitors: Present Understanding and Looking to the Future

Connolly

Stearns

2010

Curr Breast Cancer Rep

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Clinicopathologic characteristics have traditionally played a predominant role in adjuvant therapy recommendations for women with breast cancer. Host genetic factors, which impact drug metabolism, drug transportation, and drug targets, may lead to a differential treatment-related outcome in breast cancer, but their role in treatment decision-making has only recently been recognized. Genetic polymorphisms in the CYP2D6 gene and pharmacologic inhibition of the enzyme lead to an altered tamoxifen metabolism, safety profile, and possibly reduced clinical benefit. Inter-individual response to therapy has also been observed with use of aromatase inhibitors, agents that have largely superseded tamoxifen in the treatment of post-menopausal hormone receptorpositive breast cancer. We review the available evidence regarding the impact of pharmacogenetic variation on the drug-response phenotype of the aromatase inhibitors.

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Synthesis and aromatase inhibition by potential metabolites of exemestane (6-methylenandrosta-1,4-diene-3,17-dione)

Cited by 35 publications

References 11 publications

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

Pharmacogenetics of Aromatase Inhibitors: Present Understanding and Looking to the Future

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