Renal handling of drugs in the healthy elderly - Creatinine clearance underestimates renal function and pharmacokinetics remain virtually unchanged

Objective: It is commonly assumed that renal function, and in parallel the excretion of drugs, is considerably reduced in the elderly. Endogenous crea tinine clearance or indirect estimates of this parameter are generally reco mmended for adapting drug dosage. The present study evaluates the validity of both assumptions. Methods. We compared pharmacokinetics (and pharmacodynamics) of 50 mg ateno lol, 800 mg piracetam and 25 mg hydrochlorothiazide plus 50 mg triamterene in ten healthy young [25 (2) years] and 11 healthy elderly subjects [68 (5) years]. Inulin (C-in) and para-aminohippurate [PAH (C-PAH)] clearance (inf usion clearance technique), endogenous (C-Cr) and calculated (Cockroft-Gaul t) creatinine clearance, analysis of drugs and their metabolites (HPLC), we re performed. Renal haemodynamics and the pharmacokinetics of beta-adrenerg ic blocking agent, diuretics and the nootropic agent piracetam, respectivel y, were measured on separate days. Results: C-in was significantly (P < 0.01) lower in the healthy elderly sub jects [104 (12) vs 120 (14) ml . min(-2) . 1.71 m(-2) in the young], but re mained within the normal range (> 90 ml . min(-2) . 1.73 m(-2)). In contras t, C-Cr was even lower in healthy elderly subjects [95 (24) vs 121 (20) ml . min(-1) in the young], and the Cockroft-Gault clearance underestimated tr ue glomerular filtration rate (GFR) even more seriously [74 (17) vs 122 (16 ) ml . min(-1)]. For atenolol the mean area under the curve (AUC) was simil ar in both groups [3.16 (0.48) mu g . h(-1) . ml(-1) in the elderly vs 3.01 (0.30) in the young], as was the mean maximal plasma concentration [0.42 ( 0.07) vs 0.44 (0.06) mu g . ml(-1)], but the proportion of the drug excrete d in urine was marginally (P < 0.025) lower in the elderly. Similar results were obtained for hydrochlorothiazide, whereas no marked differences betwe en the groups were found for triamterene and its metabolite. Furthermore, t he pharmacodynamic action of diuretics was not significantly altered in the elderly. Conclusions: The true GFR of the healthy elderly remains within the normal range and is underestimated by creatinine clearance and more so by its surr ogate (Cockroft-Gault clearance). In parallel, pharmacokinetics of renally excreted drugs are not affected in the healthy elderly to a clinically sign ificant extent. For drugs with a narrow therapeutic window, indirect estima tes of GFR appear to be an unreliable means for calculating correct dosage in the elderly.