Crowley J J, Cusack B J, Jue S G, Koup J R, Park B K, Vestal R E
Clinical Pharmacology and Gerontology Research Unit, Veterans Administration Medical Center, Boise, Idaho.
J Pharmacol Exp Ther. 1988 May;245(2):513-23.
The effect of age on the induction of theophylline metabolism by phenytoin was examined in healthy young and old male cigarette smokers (greater than or equal to 20 cigarettes/day) and nonsmokers. Two single dose studies of theophylline pharmacokinetics were performed, one as a base-line control and another after a 2-week course of phenytoin. Phenytoin was administered as an i.v. loading dose followed by oral ingestion. The dose was adjusted to achieve total phenytoin plasma concentrations within a low therapeutic range (10-13 micrograms/ml). Free phenytoin concentrations in plasma were slightly higher in old (nonsmokers 0.84 +/- 0.13 micrograms/ml; smokers 0.89 +/- 0.12 micrograms/ml) than in young (nonsmokers 0.75 +/- 0.10 micrograms/ml; smokers 0.72 +/- 0.10 micrograms/ml) subjects, but the differences were not significant. Base-line plasma theophylline clearance was 30% lower in old compared with young nonsmokers (34.0 +/- 2.5 vs. 48.8 +/- 2.6 ml/hr/kg, P less than .001), whereas the small age difference between old and young smokers (86.0 +/- 8.4 vs. 72.4 +/- 8.0 ml/hr/kg) was not significant. Smokers had higher values of theophylline clearance than nonsmokers regardless of age. Half-life was prolonged in old nonsmokers in proportion to decreased clearance, despite a slight decrease in volume of distribution. Phenytoin induced theophylline metabolism to an equal degree in both age groups and in both smokers (young 42.6 +/- 6.5%; old 47.3 +/- 3.6%) and nonsmokers (young 56.3 +/- 8.8%; old 45.4 +/- 6.4%). The magnitude of its induction in smokers was additive to that of cigarette smoking. Old age was associated with a modest selective reduction in N-demethylated metabolic pathways to 3-methylxanthine and 1-methyluric acid, whereas smoking preferentially induced the formation of these products. Phenytoin increased the production of all theophylline primary metabolites to an equal degree in both old and young subjects. The urinary excretion of 6 beta-hydroxycortisol was not influenced significantly by age or smoking and increased 2- to 3-fold in all subject groups with phenytoin. These results confirm earlier observations of a reduction in basal oxidative capacity in elderly nonsmoking males. They also demonstrate that the ability to induce the metabolism of theophylline by smoking or phenytoin and the ability to induce the metabolism of cortisol by phenytoin are maintained in old age.
在健康的年轻和老年男性吸烟者（每天≥20支香烟）及非吸烟者中，研究了年龄对苯妥英诱导茶碱代谢的影响。进行了两项茶碱药代动力学的单剂量研究，一项作为基线对照，另一项在苯妥英治疗2周后进行。苯妥英先静脉注射负荷剂量，随后口服。调整剂量以使总苯妥英血浆浓度处于低治疗范围（10 - 13微克/毫升）内。老年受试者（非吸烟者0.84±0.13微克/毫升；吸烟者0.89±0.12微克/毫升）血浆中游离苯妥英浓度略高于年轻受试者（非吸烟者0.75±0.10微克/毫升；吸烟者0.72±0.10微克/毫升），但差异不显著。与年轻非吸烟者相比，老年非吸烟者的基线血浆茶碱清除率低30%（34.0±2.5对48.8±2.6毫升/小时/千克，P＜0.001），而老年和年轻吸烟者之间的年龄差异较小（86.0±8.4对72.4±8.0毫升/小时/千克）不显著。无论年龄如何，吸烟者的茶碱清除率值均高于非吸烟者。老年非吸烟者的半衰期因清除率降低而相应延长，尽管分布容积略有减少。苯妥英在两个年龄组以及吸烟者（年轻组42.6±6.5%；老年组47.3±3.6%）和非吸烟者（年轻组56.3±8.8%；老年组45.4±6.4%）中同等程度地诱导茶碱代谢。其在吸烟者中的诱导程度与吸烟的诱导程度相加。老年与N - 去甲基化代谢途径适度选择性降低有关，导致生成3 - 甲基黄嘌呤和1 - 甲基尿酸减少，而吸烟则优先诱导这些产物的形成。苯妥英在老年和年轻受试者中同等程度地增加了所有茶碱主要代谢产物的生成。6β - 羟基皮质醇的尿排泄不受年龄或吸烟的显著影响，在所有接受苯妥英治疗的受试者组中增加了2至3倍。这些结果证实了早期关于老年非吸烟男性基础氧化能力降低的观察结果。它们还表明，吸烟或苯妥英诱导茶碱代谢的能力以及苯妥英诱导皮质醇代谢的能力在老年时得以维持。
