Wynne H A, Yelland C, Cope L H, Boddy A, Woodhouse K W, Bateman D N
Wolfson Unit of Clinical Pharmacology, The University, Newcastle-upon-Tyne.
Age Ageing. 1993 Sep;22(5):354-9. doi: 10.1093/ageing/22.5.354.
We have investigated the association of age and frailty with the pharmacokinetics and pharmacodynamics of the conjugated drug, metoclopramide. Six healthy young, six healthy elderly (> 65 years), and six frail elderly (> 65 years) subjects were studied on two occasions, receiving 10 mg metoclopramide by intravenous bolus and orally, in random order. Blood and urine were collected for measurement of pharmacokinetic parameters. Liver volume was measured by ultrasound. Sedation and contentment were self-recorded on visual analogue scales. Liver volume was not significantly different in the three groups, nor was bio-availability of metoclopramide. Clearance was similar in the young and fit elderly but reduced in the frail elderly subjects when compared with the young (p < 0.05), both when expressed in absolute terms and per unit liver volume. There were no differences in percentages cleared as the free drug or as the sulphate or glucuronide metabolite within or between groups, suggesting that frailty can produce a general impairment of conjugation pathways. The frail elderly subjects reported more sedation after intravenous dosage than the other subjects, whilst only young subjects reported akathisia. This did not relate to pharmacokinetic differences and seemed therefore to reflect associated pharmacodynamic changes in specific receptor or target sites.
我们研究了年龄和虚弱状态与复方药物甲氧氯普胺的药代动力学和药效学之间的关联。研究了六名健康青年、六名健康老年人（>65岁）和六名虚弱老年人（>65岁），分两次进行，随机给予10mg甲氧氯普胺静脉推注和口服。采集血液和尿液以测量药代动力学参数。通过超声测量肝脏体积。镇静和满足感通过视觉模拟量表进行自我记录。三组的肝脏体积无显著差异，甲氧氯普胺的生物利用度也无显著差异。年轻和健康老年人的清除率相似，但与年轻人相比，虚弱老年人的清除率降低（p<0.05），无论是以绝对值还是以单位肝脏体积表示。各组内或组间以游离药物或硫酸盐或葡萄糖醛酸代谢物形式清除的百分比无差异，这表明虚弱可能导致结合途径的普遍受损。与其他受试者相比，虚弱老年人静脉给药后报告的镇静作用更强，而只有年轻受试者报告有静坐不能。这与药代动力学差异无关，因此似乎反映了特定受体或靶点部位相关的药效学变化。
