AGE-RELATED DIFFERENCE IN TAMOXIFEN DISPOSITION

Purpose: To investigate the pharmacokinetic aspects of tamoxifen, such as the pharmacokinetic-pharmacodynamic (toxicity and clinical respons e) relationship and the influence of hepatic dysfunction, age, treatme nt duration, and associated chemotherapy on tamoxifen pharmacokinetics . Patients and methods: Three hundred sixteen patients with breast can cer (247 postmenopausal women) were investigated. Mean age was 58 year s (age range, 29 to 85 years). One hundred seventeen patients received tamoxifen as single therapy (adjuvant, 60; neoadjuvant, 17; metastati c, 40); 292 of 316 received 30 mg daily. We obtained 794 blood samples at steady state. Tamoxifen and metabolites, N-desmethyltamoxifen, N-d esdimethyltamoxifen, primary alcohol, and 4-hydroxytamoxifen were meas ured HPLC. Results: Serum concentrations of tamoxifen and metabolites showed a wide asymmetrical distribution. Median and extremes were 347 nmol/L (not detectable [ND] to 1677) for tamoxifen, 572 nmol/L (ND to 3132) for N-desmethyltamoxifen, 109 nmol/L (ND to 795) for N-desdimeth yltamoxifen, and 59 nmol/L (ND to 390) for primary alcohol. 4-Hydroxyt amoxifen was detectable in 9.5% of the samples (ND to 162 nmol/L). Nei ther the absolute nor the relative concentrations of each compound sho wed significant variations during treatment. Chemotherapy concomitant with tamoxifen slightly increased the tamoxifen blood concentration, H epatic dysfunction had no obvious effect on drug concentrations, an ex ception being a slight reduction in the relative proportion of tamoxif en. The influence of age revealed that concentrations of tamoxifen and metabolites increased significantly with age: women younger than 40 y ears had a tamoxifen plus metabolite median concentration of 802 nmol/ L compared with 2428 nmol/L for women older than 80 pears. In the 28 p atients in whom tamoxifen-related side effects developed, the proporti on of demethylated metabolites was higher than that in patients in who m toxicity did not develop. There was no difference in drug concentrat ions between responding and nonresponding patients. Conclusion: Despit e the tremendous interpatient variability in drug concentrations, the present data show that tamoxifen and metabolite concentrations signifi cantly increase with age.