Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects

Abstract

AimsThe prevalence of hyperuricaemia and gout increases with age as does the incidence of adverse effects to allopurinol, the major uric acid lowering drug. The present study was performed to compare the disposition and effects of allopurinol and its active metabolite oxipurinol in elderly and young subjects without major health problems. Methods Ten elderly (age range 71-93 years) and nine young subjects (24-35 years) received an oral dose of 200 mg allopurinol in an open, single dose, cross sectional design. Four of these individuals were additionally dosed with 200 mg allopurinol intravenously. Plasma and urine concentrations of allopurinol, oxipurinol, hypoxanthine, xanthine, and uric acid were measured by h.p.l.c. Results Total clearance of allopurinol was not different in elderly (15.7±3.8 ml min −1 kg −1 , mean±s.e. mean) and young subjects (15.7±2.1), whereas total clearance of oxipurinol was significantly reduced in the aged (0.24±0.03) compared with young controls (0.37±0.05) as was the distribution volume of oxipurinol (0.60±0.09 and 0.84±0.07 l kg −1 , respectively). Oxipurinol was eliminated primarily by the kidneys, allopurinol by metabolism. Fractional peroral bioavailability of allopurinol was 0.81±0.16 (n=4, two elderly and two young subjects). Although maximal plasma concentrations of oxipurinol were significantly higher in elderly (5.63±0.83 mg ml −1 ) than in young persons (3.75±0.25) as was the area under the oxipurinol plasma concentration-time curve, AUC (260±46 and 166±23 mg ml −1 h, respectively), the pharmacodynamic effect of oxipurinol was smaller in elderly than young subjects (time-dependent decrease of plasma uric acid 83±30 mg ml −1 h in elderly compared with 176±21 in young controls). Oxipurinol increased the renal clearance of xanthine, suggesting inhibition of tubular xanthine reabsorption by oxipurinol. Conclusions Although allopurinol elimination is not reduced in the aged, that of its active metabolite oxipurinol is because of an age-dependent decline in renal function. Xanthine oxidase inhibition by oxipurinol appears to be reduced in old age. In addition to its uricostatic action, oxipurinol has a xanthinuric effect which is also diminished in the elderly.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…Oxypurinol is approximately 10-times less potent an inhibitor of the target enzyme, xanthine oxidase (Tamta et al, 2006); however, the circulating concentrations of oxypurinol in humans following allopurinol administration are far greater and sustained for a longer time. Maximal concentrations of oxypurinol are about 4-to 5-fold greater, and the half-life of parent and metabolite are 1 and 20 hours, respectively (Turnheim et al, 1999;Day et al, 2007). Thus, the contribution of oxypurinol to xanthine oxidase inhibition activity dominates at later timepoints.…”

Involvement of Uric Acid Transporter in Increased Renal Clearance of the Xanthine Oxidase Inhibitor Oxypurinol Induced by a Uricosuric Agent, Benzbromarone

“…Previous observations, that approximately 80% of glomerularly filtered oxypurinol is reabsorbed (Turnheim et al, 1999) and that benzbromarone is a strong inhibitor of URAT1-mediated transport of uric acid (Enomoto et al, 2002), suggest the involvement of a transporter such as URAT1 in the reabsorption of oxypurinol, and inhibition of the transporter by benzbromarone could explain the drug interaction between oxypurinol and benzbromarone. Accordingly, the present study was mainly focused on URAT1, although attention was also paid to another apical membrane transporter, OAT4, which is classified into the SLC22A family (as is URAT1) and is expressed at the apical membrane of renal tubular epithelial cells (Ekaratanawong et al, 2004) as well as organic cation/carnitine transporters OCTN1 and OCTN2, which are also expressed at the apical membrane and transport xenobiotics (Tamai et al, 2001(Tamai et al, , 2004.…”

“…Fractional excretion of oxypurinol is about 20% of glomerular filtration in humans, and oxypurinol shows negligible binding to plasma protein (Elion et al, 1966). This observation suggests that about 80% of oxypurinol is reabsorbed after glomerular filtration, although the reabsorption mechanism remains to be clarified (Colin et al, 1986;Yamamoto et al, 1991;Turnheim et al, 1999). Furthermore, concomitant use of benzbromarone and probenecid caused an increase in the renal clearance and a decrease in plasma concentration of oxypurinol (Colin et al, 1986;Yamamoto et al, 1991;Muller et al, 1993).…”

High-Dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid

“…34 Another study in healthy elderly patients found that oxypurinol (but not allopurinol) clearance is reduced compared with younger subjects. 35 More studies are required to assess this risk fully. Our study is, at least, very encouraging, even if the number studied is too small to be fully reassuring on safety.…”