Hunt C M, Westerkam W R, Stave G M, Wilson J A
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Mech Ageing Dev. 1992 Jun;64(1-2):189-99. doi: 10.1016/0047-6374(92)90106-n.
Elderly patients exhibit decreased clearance of multiple drugs biotransformed by the hepatic cytochromes P-450. The cytochromes P-450 are a superfamily of enzymes, which comprise a central component of phase I drug metabolism. Distinct isoforms metabolize specific drugs. In human liver microsomes, the glucocorticoid-inducible cytochrome P-450IIIA, CYP3A, catalyzes the N-demethylation of erythromycin. To examine the activity of hepatic CYP3A in elderly males and females, erythromycin N-demethylation was examined, as reflected by the recently described [14C]erythromycin breath test in 24 healthy volunteers, age 70-88. The [14C]erythromycin breath test was measured in normal elderly males and females to: (a) determine persistence of the gender-related dimorphism (evident in younger subjects) of CYP3A activity in the elderly population, (b) examine the effect of % ideal body weight, age, diet, and medication use on the activity of human hepatic CYP3A, and (c) compare breath test results obtained in normal geriatric volunteers with published results obtained in younger subjects, to determine aging-related alterations in CYP3A enzyme activity. Erythromycin N-demethylation varied fivefold among these patients. Similar to earlier studies examining erythromycin N-demethylation in younger subjects, CYP3A activity was found to vary with gender in the geriatric cohort. [14C]Erythromycin N-demethylation at 60 min was 3.14% +/- 0.75 (n = 13) in females and 2.15% +/- 0.77 (n = 11) in males (P = 0.005). In evaluating the role of % ideal body weight and % dietary fat using multivariable linear regression analyses, [14C]erythromycin N-demethylation, was found to decline significantly as % ideal body weight increased (P = 0.001). This was not confounded by gender. [14C]Erythromycin N-demethylation was not related to dietary fat intake (P less than 0.13). [14C]Erythromycin N-demethylation in the elderly volunteers was similar to values reported for subjects aged 20-60. Performance of a new non-invasive test of the human hepatic glucocorticoid-inducible CYP3A in a geriatric cohort suggests that: (a) the gender-related heterogeneity in function of the glucocorticoid inducible human CYP3A persists during normal aging, (b) that the activity of CYP3A may decrease in obesity, and (c) that the activity of CYP3A is stable throughout normal ageing.
老年患者对多种经肝脏细胞色素P - 450进行生物转化的药物清除率降低。细胞色素P - 450是一类酶的超家族，是I相药物代谢的核心组成部分。不同的同工酶代谢特定的药物。在人肝微粒体中，糖皮质激素诱导的细胞色素P - 450IIIA，即CYP3A，催化红霉素的N - 去甲基化。为了研究老年男性和女性肝脏CYP3A的活性，对红霉素N - 去甲基化进行了检测，这通过最近描述的[14C]红霉素呼气试验在24名70 - 88岁的健康志愿者中得以体现。对正常老年男性和女性进行[14C]红霉素呼气试验的目的是：(a)确定老年人群中CYP3A活性与性别相关的二态性（在年轻受试者中明显）是否持续存在，(b)研究理想体重百分比、年龄、饮食和药物使用对人肝脏CYP3A活性的影响，以及(c)将正常老年志愿者的呼气试验结果与年轻受试者已发表的结果进行比较，以确定与衰老相关的CYP3A酶活性变化。这些患者中红霉素N - 去甲基化的差异达五倍之多。与早期在年轻受试者中检测红霉素N - 去甲基化的研究相似，在老年队列中发现CYP3A活性随性别而变化。60分钟时女性的[14C]红霉素N - 去甲基化率为3.14%±0.75（n = 13），男性为2.15%±0.77（n = 11）（P = 0.005）。在使用多变量线性回归分析评估理想体重百分比和膳食脂肪百分比的作用时，发现[14C]红霉素N - 去甲基化率随着理想体重百分比的增加而显著下降（P = 0.001）。这不受性别的影响。[14C]红霉素N - 去甲基化与膳食脂肪摄入量无关（P < 0.13）。老年志愿者的[14C]红霉素N - 去甲基化与20 - 60岁受试者报道的值相似。在老年队列中对人肝脏糖皮质激素诱导的CYP3A进行一项新的非侵入性检测表明：(a)糖皮质激素诱导的人CYP3A功能中与性别相关的异质性在正常衰老过程中持续存在，(b)CYP3A活性在肥胖时可能降低，以及(c)CYP3A活性在整个正常衰老过程中是稳定的。
