The use of aromatase inhibitors in boys with short stature: what to know before prescribing?

Abstract

Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.

Figure 1. Anastrozole metabolic pathways. Anastrozole can be coupled directly to glucuronide-N-anastrozole or previously converted to hydroxyanastrozole via cytochrome P450 (CYPs) and subsequent conjugation to glucuronide-OH-anastrozole. In addition, anastrozole can undergo dealkylation by CYP3A4, thereby releasing the triazole ring. The main isoforms involved in anastrozole metabolic pathways are in bold. CYP3A4, CYP3A5, and CYP2C8: cytochrome P450 isoforms. UGT1A4 and UGT2B7: uridine glucuronyl transferase (UGT) isoforms.

Figure 2. Letrozole metabolic pathways. Letrozole is converted previously to carbinol via cytochrome P450 (CYPs) and then, subsequently, the carbinol is conjugated to a glucuronide. Letrozole can undergo dealkylation, thus releasing the triazole ring. The main isoforms involved in the metabolic pathways are in bold. CYP2A6 and CYP3A4: cytochrome P450 isoforms. UGT2B7: uridine glucuronyl transferase (UGT) isoform.