The Effect of Age and Acetylator Phenotype on the Pharmacokinetics of Sulfasalazine in Patients with Rheumatoid Arthritis

Abstract

The pharmacokinetic disposition of sulfasalazine and its metabolites was studied in 8 young and 12 elderly patients with active rheumatoid arthritis. Equal numbers of slow and fast acetylators were included in each age group. Patients received enteric-coated sulfasalazine 2g daily for 21 days; specimens of serum and urine were collected for 96 h after administration on days 1 and 21. The elimination half-life of sulfasalazine was greater in the elderly patients. Many disposition parameters of sulfapyridine differed in slow and fast acetylators; of greatest significance were the increased values of steady-state serum concentration in the slow acetylators. There was no effect of age on any sulfapyridine disposition parameters. Values for the steady-state serum concentrations of N-acetyl-5-acetylsalicylic acid were greater in elderly than in young patients. The metabolism of sulfapyridine was markedly affected by acetylator phenotype and this was reflected in the composition of sulfapyridine-related material in the urine. Thus, age is a determinant of the steady-state concentrations of salicylate moieties but acetylator phenotype plays a greater role in determining the serum concentration of sulfapyridine, which has greater therapeutic implications in rheumatology.

Clinical Pharmacokinetics of Slow-Acting Antirheumatic Drugs

“…The terminal elimination half-life of sulphasalazine in groups of patients with rheumatoid arthritis and with inflammatory bowel disease ranged from 3 to 9 hours (Astbury et al 1990). Elimination half-life was prolonged in the elderly (Taggart et al , 1992. It is probably not just renal function deteriorating with age which is causing this lower elimination rate, since only a small fraction of an administered dose of sulphasalazine is reported to be excreted unchanged in the urine (Pinals 1988).…”

“…The Caucasian population is reported to show bimodal distribution of acetylators, with approximately equal proportions of fast and slow acetylators (Bachrach 1988;Khan et al 1983). The terminal elimination half-life of sulphapyridine in slow acetylators is about 50 to 100% longer than in fast acetylators (Taggart et al , 1992. Slow acetylators have significantly higher plasma concentrations of sulphapyridine, which has been proposed to be related to a higher prevalence of minor adverse effects in such patients (Pinals 1988;Taggart 1987;Taggart et al 1992).…”

“…The terminal elimination half-life of sulphapyridine in slow acetylators is about 50 to 100% longer than in fast acetylators (Taggart et al , 1992. Slow acetylators have significantly higher plasma concentrations of sulphapyridine, which has been proposed to be related to a higher prevalence of minor adverse effects in such patients (Pinals 1988;Taggart 1987;Taggart et al 1992). In clinical practice it is not yet recommended that acetylator status be determined before starting therapy.…”

Pharmacokinetic consideration of synthetic DMARDs in rheumatoid arthritis

“…Trials that had compared individual daily doses of 2 and 3 g SSZ reported that the therapeutic efficacy was comparable [73]. Age as well as the acetylator status influences the achievement of a steady state of drug concentration [74,75]. The mechanism by which the SSZ is effective in RA is explained by its pleiotropic effect on different limbs of immune system like T-cell, synoviocytes and adenosine pathway (Tables 1 and 2) [76][77][78].…”

Pharmacokinetic dosage guidelines for elderly subjects

“…1 [156] Sildenafil *, ‡ 1! 22.0 11.4 [157] Sufentanil 1 20.7 21.6 [158] Sulfasalazine * , fast & slow acetylators -1.4 -0.2 1.0 -0.47 [159] Teicoplanin < 0.2 0.19 0.18 [160] Telmisartan *, ‡ -1 2 . 1 1 4 .…”