1 Oncology Unit INRCA, Rome; 2 Oncology Unit IST, Genoa; 3 Pharmacology IST, Genoa; 4 Geriatric Department "La Sapienza", University of Rome, Rome, Italy
*E-mail: l.repetto@inrca.it
Concomitant use of hormone therapy and antihypertensive therapy in elderly women is compelled by a high prevalence of breast cancer with hypertension [1]. However, very little is known about the possible interaction of combined treatment and older patients represent a high-risk group due to declining renal function and liver metabolism. Previous research into the effect of aromatase enzyme activity using angiotensin-converting enzyme (ACE) inhibitors has been predominantly carried out on animal models. ACE inhibitors have been shown to cause a decrease in 17 ß-oestradiol production and an increase in androgen production, while angiotensin II (ANG II) causes an increase in 17 ß-oestradiol production and a decrease in androgen levels. This analysis of aromatase enzyme activity has shown that the latter is positively regulated by ANG II and negatively by ACE. It can be concluded that ACE and ANG II activity independently modulate aromatase activity and this suggests a new physiological role for ACE and ANG II [2].
In this study, we evaluated the pharmacokinetic interaction of combined treatment with anastrozole and quinapril in elderly women affected by breast cancer requiring hormonal treatment, and moderate hypertension. We enrolled five women affected by breast cancer and moderate hypertension (grade 2; WHO-ISH guidelines [3]), who had been free from treatment for 4 weeks, and five women with breast cancer without hypertension. The average age was 77 ± 7 years.
The following treatments were administered and blood samples collected. Group A: five patients were treated with anastrozole for at least 10 weeks; blood samples (6 ml of heparinized blood) were taken before starting treatment (time 0), and after 21, 28, 42, 56 and 70 days of therapy. Group B: five patients were treated with anastrozole for 10 weeks; after 4 weeks they received quinapril for 28 days; blood samples were taken at the same time as group A. Blood pressure was measured at the time of entry, before starting quinapril and twice a day during the 4 weeks of treatment with ACE inhibitor.
Primary assessment was the steady-state plasma anastrozole concentrations following once-daily anastrozole alone or anastrozole plus quinapril. The evaluation of plasma anastrozole concentrations started after 21 days of drug administration, to ensure the steady-state had been obtained. Blood samples were taken from each patient 12 h after each dose of anastrozole: at days 21 and 28 for baseline measurements; days 42 and 56 for on-treatment measurements; and day 70 for post-treatment evaluation.
Anastrozole analysis in plasma was carried out according to the Bock et al. validated method of solvent extraction, capillary gas chromatography separation and electron capture detection [4]. The plasma levels of quinapril and of its active metabolite, quinaprilat, were determined according to the method of Hengy and Most [5]. Plasma levels of anastrozole and quinapril were analysed using validated methods. The sensitivity limit was 3 ng/ml.
Comparisons of the plasma anastrozole levels between the two groups were obtained through the non-parametric MannWhitney test. The mean plasma anastrozole concentration in group A was 59.2 ng/ml on day 21 and 62.6 ng/ml on day 56. For group B, the mean concentration was 49.43 ng/ml on day 21 and 49.80 ng/ml on day 56. None of the mean values were significant at a 5% confidence level (Table 1).
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L. Repetto1,2*, O. Vannozzi3, A. Hazini2, A. Sestini4, M. Pietropaolo4 & R. Rosso2
1Oncology Unit Instituto Nazionale di Riposo e Cura per Anziani, Rome; 2Oncology Unit IST, Genoa; 3Pharmacology Instituto Nazionale per la Ricerca sul Cancro, Genoa; 4Geriatric Department La Sapienza, University of Rome, Rome, Italy (*E-mail: l.repetto@inrca.it)
References
1. Repetto L, Venturino A, Vercelli M et al. Performance status and comorbidity in elderly cancer patients compared with young patients with neoplasias and elderly patients without neoplastic condition. Cancer 1998; 82: 760765.[CrossRef][ISI][Medline]
2. Miano A, Gobbetti A, Zerani M. Different modulation of aromatase activity in frog testis in vitro by ACE and ANG II. Am J Physiol 1999; 277: R1261R1267.[ISI][Medline]
3. 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. Guidelines Subcommittee. J Hypertens 1999; 17: 151183.[CrossRef][ISI][Medline]
4. Bock MJH, Bara I, LeDonne N et al. Validated assay for the quantification of anastrozole in human plasma by gas chromatography-63Ni electron capture detection. J Chromatogr 1997; 700: 131138.
5. Hengy H, Most M. Determination of the new ACE inhibitor quinapril and its active metabolite quinaprilate in plasma and urine by high performance liquid chromatography and pre-column labelling for fluorescent-detection. J Liq Chromatogr 1998; 11: 517530.