Clinical Pharmacokinetics and Pharmacodynamics of Allopurinol and Oxypurinol

Abstract

Allopurinol is the drug most widely used to lower the blood concentrations of urate and, therefore, to decrease the number of repeated attacks of gout. Allopurinol is rapidly and extensively metabolised to oxypurinol (oxipurinol), and the hypouricaemic efficacy of allopurinol is due very largely to this metabolite. The pharmacokinetic parameters of allopurinol after oral dosage include oral bioavailability of 79 +/- 20% (mean +/- SD), an elimination half-life (t((1/2))) of 1.2 +/- 0.3 hours, apparent oral clearance (CL/F) of 15.8 +/- 5.2 mL/min/kg and an apparent volume of distribution after oral administration (V(d)/F) of 1.31 +/- 0.41 L/kg. Assuming that 90 mg of oxypurinol is formed from every 100mg of allopurinol, the pharmacokinetic parameters of oxypurinol in subjects with normal renal function are a t((1/2)) of 23.3 +/- 6.0 hours, CL/F of 0.31 +/- 0.07 mL/min/kg, V(d)/F of 0.59 +/- 0.16 L/kg, and renal clearance (CL(R)) relative to creatinine clearance of 0.19 +/- 0.06. Oxypurinol is cleared almost entirely by urinary excretion and, for many years, it has been recommended that the dosage of allopurinol should be reduced in renal impairment. A reduced initial target dosage in renal impairment is still reasonable, but recent data on the toxicity of allopurinol indicate that the dosage may be increased above the present guidelines if the reduction in plasma urate concentrations is inadequate. Measurement of plasma concentrations of oxypurinol in selected patients, particularly those with renal impairment, may help to decrease the risk of toxicity and improve the hypouricaemic response. Monitoring of plasma concentrations of oxypurinol should also help to identify patients with poor adherence. Uricosuric drugs, such as probenecid, have potentially opposing effects on the hypouricaemic efficacy of allopurinol. Their uricosuric effect lowers the plasma concentrations of urate; however, they increase the CL(R) of oxypurinol, thus potentially decreasing the influence of allopurinol. The net effect is an increased degree of hypouricaemia, but the interaction is probably limited to patients with normal renal function or only moderate impairment.

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.…”

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

“…7) (Tamta et al, 2006). Although the metabolite is less potent than the parent (approximately 10-fold lower potency than the parent), it has a longer half-life and higher circulating concentrations compared with the parent, allowing the metabolite to contribute to the overall activity of the parent (Day et al, 2007).…”

Management of Hyperuricemia and Gout

“…Thus, these data suggest that the combination of allopurinol and probenecid might be an effective way to reduce serum uric acid levels and prevent recurrent acute gouty episodes in patients with no contraindications to uricosuric drugs. Since simple methods are available to monitor allopurinol and oxypurinol in human serum, this methodology might be very useful for the detection of the toxic levels of these drugs and for the determination of the range of concentrations causing adverse reactions [ 644,645 ] . The long-term use of this combined therapy has not been evaluated, and the possible adverse reactions from such a treatment regimen remain to be assessed.…”