About this pathway
Background
Letrozole is a non-steroidal aromatase inhibitor used in the adjuvant treatment of postmenopausal patients with estrogen receptor–positive breast cancer (for the pharmacodynamic pathways see Aromatase Inhibitor Pathway (Breast Cell), Pharmacodynamics and Aromatase Inhibitor Pathway (Multiple Tissues), Pharmacodynamics ).
Metabolism
Letrozole undergoes metabolism in the liver by CYP2A6 and CYP3A4 to form an inactive carbinol metabolite [Articles:21975350, 23965986, 30094551, 34096894]. It undergoes secondary metabolism by UGT2B7 to form letrozole carbinol glucuronide [Article:23965986]. Letrozole carbinol glucuronide is the major metabolite of letrozole comprising about 65% of the drug and metabolites in urine [Article:23965986].
Pharmacogenomics
Letrozole is not currently on the CPIC list for guideline evaluation, and CYP2A6 is not a gene with CPIC assigned standardized allele functions or metabolizer phenotypes.
The FDA and HCSC labels mention CYP2A6 in the context of metabolism but do not have pharmacogenomic information on variants of CYP2A6 (see annotated labels for FDA and HCSC and hormone receptors). The Japanese drug label for letrozole is annotated for CYP2A6 and gives pharmacokinetic information about non-standardized phenotypes: “mean plasma trough concentration was approximately 2-fold higher in SMs than in EMs.” where “slow metabolizers (SMs) who were deficient for CYP2A6, the enzyme responsible for drug metabolism, or had a combination of genotypes associated with reduced enzyme activity (CYP2A6*4, CYP2A6*7, CYP2A6*9 and CYP2A6*10) as well as in extensive metabolizers (EMs) who had wild-type genotypes, CYP2A6*1A or CYP2A6*1B”. These likely correspond to the old CYP allele nomenclature database alleles (see PharmVar and [Article:39051767] for current allele mappings).
Reactions & interactions (5)
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Biochemical Reaction
letrozole carbinol → letrozole carbinol glucuronide
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Biochemical Reaction
letrozole → letrozole carbinol
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Catalysis
UGT2B7 → Biochemical Reaction
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Catalysis
CYP2A6 → Biochemical Reaction
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Catalysis
CYP3A4 → Biochemical Reaction
Edit history (1)
- 2024-08-01 Create