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Modifying Drugs 478 Annals ofthe Rheumatic Diseases 1996; 55: 478-481 Urinary glucaric acid excretion in rheumatoid Ann Rheum Dis: first published as 10.1136/ard.55.7.478 on 1 July 1996. Downloaded from arthritis: influence of disease activity and disease modifying drugs R Addyman, C Beyeler, C Astbury, H A Bird Abstract of drug toxicity as much as possible, especially Objective-To examine if a correlation in view of the polypharmacy that is common. exists between cytochrome P-450 enzyme Against the background of the subject's induction and disease activity in patients genetic constitution, drug metabolism- with rheumatoid arthritis (RA), measuring involving different enzyme systems of bio- urinary excretion of D-glucaric acid (GA) transformation-is affected by many variables as an index ofphase II drug metabolism. such as age, gender, diet, smoking, other Methods-Patients with RA were treated environmental factors, and drugs,' 2 and also with sulphasalazine, sodium aurothio- by hepatic and extrahepatic diseases such as malate, or D-penicillamine in standard diabetes mellitus, thyroid disease, cardiopul- dose regimens, for 24 weeks. Patients monary dysfunction, and malignancy. Phase I with ankylosing spondylitis (AS) or non- drug metabolism involves the mixed function inflammatory arthritis (NIA) acted as oxidase enzyme, cytochrome P-450, and is controls. The urinary GA:creatinine ratio considered to be the principal drug metabol- was measured at 0, 12, and 24 weeks of ising enzyme system. Located predominantly treatment. on the smooth endoplasmic reticulum, it Results-Patients with RA had a slightly catalyses the oxidation of a wide variety of greater urinary GA:creatinine ratio than compounds and it can be induced or inhibited patients with AS or NIA at baseline; this by a wide range of chemically unrelated increased during treatment with disease substances, including drugs.2 This is followed modifying antirheumatic drugs (DMARDs). by a change in drug efficacy and toxicity, Sulphasalazine treatment had a greater especially for drugs with a small therapeutic effect on GA excretion than sodium ratio and with long term application, necessi- aurothiomalate or D-penicillamine; this tating an alteration in the dosage schedule. http://ard.bmj.com/ difference was statistically significant States of inflammation also may affect the between weeks 0 and 12 (p = 0-01). Gamma rate of drug metabolism. In man, it has been glutamyltranspeptidase concentration shown that fever induced by the steroid showed a weak correlation with GA excre- pyrogen etiocholanolone or injected endotoxin tion between weeks 0 and 12 (p = 0.03), but is followed by impaired hydroxylation of all other measurements of changes in antipyrine, conjugation of bromosulphthalein, disease activity (plasma viscosity, C and glucuronidation of salicylamide. Acute on October 10, 2021 by guest. Protected copyright. reactive protein, platelets, and articular viral infections and influenza vaccination can index) were found not to correlate with impair cytochrome P-450 dependent oxidative GA excretion between weeks 0-12 or 0-24. drug metabolism leading to toxicity of theo- Conclusion-The increased excretion of phylline, phenytoin, and warfarin. In animal GA in patients with RA receiving DMARD models with adjuvant arthritis, a marked treatment is probably the result of an in- impairment of drug metabolism in vitro and in Clinical Pharmacology direct effect on hepatic metabolism bearing vivo has been shown.35 Unit (Rheumatism no relationship to disease activity. There is a need to explore other hepatic Research), Chapel Allerton Hospital, metabolic systems including phase II meta- Leeds, United (Ann Rheum Dis 1996; 55: 478-481) bolism-which involves the conjugation of Kingdom oxidised drugs with an ionisable compound, R Addyman Rheumatoid arthritis C Astbury (RA) is the most such as glucuronide or sulphate-as these H A Bird common inflammatory rheumatic disease of systems may act as markers of disease activity Department of unknown aetiology, characterised by persistent or predict disease response in RA. One such Rheumatology, synovitis and complicated by local destruction urine marker of phase II metabolism is University Hospital, of bone and cartilage and various systemic D-glucaric acid (GA), already shown to be CH-3010 Berne, Switzerland manifestations. Its treatment, usually over altered in patients with RA.6 Sugars, including C Beyeler long periods, comprises compounds pro- glucose and galactose, are broken down by Correspondence to: viding symptomatic relief (analgesics, non- a catabolic pathway producing GA from Dr H A Bird, steroidal anti-inflammatory drugs (NSAIDs)) D-glucuronic acid, which can be measured in Clinical Pharmacology Unit, Chapel Allerton Hospital, and disease modifying anti-rheumatic drugs urine. There is also evidence that this step in Chapeltown Road, (DMARDs) with a later onset effect (sodium the pathway may act as an indicator of Leeds LS7 4SA, United Kingdom. aurothiomalate, D-penicillamine, sulphasala- enhanced metabolism induced by drugs. Accepted for publication zine, and others). The aim of treatment is to Drugs affecting the pathway in either man or 27 February 1996 improve disease activity and to reduce the risk animals include phenobarbitone, amidopyrine, Urinary glucaric acid excretion in rheumatoid arthritis 479 progesterone, thiopentone, organochloride Control subjects comprised patients with pesticides, diphenytoin, rifampicin, and the ankylosing spondylitis (AS) (n = 13) anti-inflammatory, phenylbutazone.7 8 (according to the modified New York Ann Rheum Dis: first published as 10.1136/ard.55.7.478 on 1 July 1996. Downloaded from Other factors clearly influence the system. criteria'6), four of whom were receiving enteric Urinary excretion of GA varies between men coated sulphasalazine before they entered the and women (53 (SD 10) ,umoV24 h and 41 (8) study. A second control group comprised ,umolV24 h, respectively) though it is not patients with non-inflammatory arthritis (NIA) influenced by the menstrual cycle.9 Excretion (n = 16), characterised by normal plasma is increased twofold in pregnancy and 3-5-fold viscosity and serum concentration ofC reactive in diabetes mellitus, but decreases in neoplastic protein (CRP), including patients with non- disease.'0 Urinary output of GA is also articular rheumatism (n = 7), osteoarthritis increased in acute viral hepatitis. Fasting (n = 5), cervical spondylosis (n = 2), low back reduces excretion twofold within two days,8 pain (n = 1), and Sudeck's atrophy (n = 1), or while chronic cardiac insufficiency, burns, and a combination of these conditions. folic acid status all influence metabolism. Patients attended a special clinic at weeks 0, There is a correlation between GA and total 12, and 24. A variety of clinical assessments liver concentration of cytochrome P-450." 12 were performed, including those of the Ritchie Clearly, GA excretion is also influenced by articular index and early morning stiffness. renal function; coefficients of variation as high Haematological assessments included haemo- as 37% and 27% have been described.9' globin and platelet count, and biochemical Adjustment of estimates of GA excretion by assessments of disease activity included plasma expressing it as a proportion of creatinine viscosity, CRP and gamma glutamyl output in a 24 hour urine sample allows the transpeptidase (GGT) concentrations. At each best option of correcting for incomplete visit, the patient provided a 24 hour urine speci- collection and, possibly, renal function.'4 men for estimation of GA:creatinine ratio. We have investigated GA excretion in The volume of each 24 hour urine sample patients with RA treated with three different was measured and aliquots frozen and stored DMARDs in order to determine the influence, at -20°C until required for analysis. Urinary if any, of different drug treatments and the glucaric acid was determined by the method extent to which excretion correlates with of Simmons et al: 16 a spectrophotometric conventional indices of rheumatoid disease assay involving inhibition of P-glucuronidase/ activity. It also remains a possibility that phenophthalein glucuronide hydrolysis by enhanced GA excretion in RA, if confirmed, D-glucaro-1,4-lactone, the latter being the may be brought under control with drug product ofurinary GA hydrolysis at 100°C and treatment and might provide an indication pH 3-6. Urinary creatinine was measured by a either of hepatic function or of enzyme standard spectrophotometric assay. The GA: induction in patients with this disease. creatinine ratio was calculated (intra-assay precision 3-29%, interassay precision 9-98%). http://ard.bmj.com/ Statistical treatment of data included Patients and methods Spearman rank correlation, Wilcoxon signed Fifty seven patients with RA (12 men and 45 rank test, Mann-Whitney U test and Kruskal- women: age range 29-80 years (mean 59-8 Wallis analysis of variance as appropriate. All (SD 12-5) years)) were recruited to the study. tests were performed using Unistat IV statis- Twenty nine patients were recruited to serve as tical software on a personal computer. controls: 12 men and one woman with AS (age on October 10, 2021 by guest. Protected copyright. range 28-55 years (mean 45-4 (8-8) years)), and five men and 11 women with NIA (age Results range 40-71 years (mean 56-6 (10-8) years)). Among the 57 patients with RA, 19 received Patients with RA met the revised criteria of sulphasalazine, 16 received D-pencillamine, the American Rheumatism
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