Pyrazinamide (PZA)
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1268 Pharmacologic evaluation of the renal handling of uric acid and oxypurines KINYA HIROSHIGE, MASAYUKI TAKASUGI, KOUGI YUU, and AKIO KUROIWA 2nd Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Kitakyushu city, Fukuoka, Japan Key words: uric acid, hypoxanthine, xanthine, idiopathic renal hypouricemia The effect of drugs that alter the renal tubular transport of urate in the renal excretion of the oxypurines, hypoxanthine (Hx) and xanthine (‡]), was used to analyze the tubular mechanisms involved in oxypurine excretion in normal subjects and in patients with idiopathic renal hypouricemia. In healthy subjects, administration of the drugs, benzbromarone (Bb) and probenecid (Pb), brought a marked uricosuric effect, but did not alter oxypurine excretion. One of 2 hypouricemic patients exhibited no uricosuric effects with Bb and the other showed a slight uricosuric effect with the drug. Bb administration, however, produced no increase in oxypurine excretion in either patient. In healthy subjects, adminis tration of pyrazinamide (PZA) suppressed the excretion of urate and oxypurines to varying degrees: relative to the baseline values, the fraction excretion of urate was reduced by 95% or more, that of Hx by about 24%, and that of X by about 64%. In patients with hypouricemia, the effects of PZA on urate and oxypurine excretion were impaired. According to these findings, we can speculate that the oxypurines have the same renal secretory mechanism as uric acid. However, the reabsorptive mechan isms of oxypurines at the postsecretory site are likely to differ from that of uric acid. Introduction aration techniques and the effects of preliminary According to the many investigations using diet [10, 11]. We now report the results of meta probenecid (Pb), pyrazinamide (PZA), and benz bolic studies, conducted on healthy subjects and bromarone (Bb), the urate transport mechanism on patients with idiopathic renal hypouricemia. In in the proximal tubule involves the following these studies, we used our HPLC method to inves sequences: (1) glomerular filtration, (2) complete tigate the renal transport mechanisms of oxypurines presecretory reabsorption, (3) tubular secretion, by observing the effects of the uricosuric agents, and (4) postsecretory reabsorption distal to the Bb and Pb, and the strong antiuricosuric agent, secretory site [1-4]. However, there is no general PZA, on oxypurine excretions. agreement about the transport mechanisms for the oxypurines, which are precursors of uric acid (UA) Materials and Methods [5, 6]. Until recently, there was no sensitive and Chemical and Assay rapid detection method for measuring oxypurines Standard of hypoxanthine (Hx), xanthine (‡]), [7, 8]. To achieve accurate oxypurine measurement, and UA were purchased from Sigma Chemical it was necessary to develop suitable conditions of Co. (St. Louis, MO, USA). PZA, Bb, and Pb sample preparation and to evaluate the effects of were provided by Sankyo (Tokyo, Japan), Torii dietary factors on oxypurine concentrations [9]. We have previously described the development (Tokyo), and Kaken (Kyoto, Japan), respectively. Other chemicals used were purchased from Wako and application of an isocratic high-performance Pure Chemicals Ltd. (Osaka, Japan). liquid chromatography (HPLC) method with high Plasma and urinary concentrations of UA and sensitivity and resolution for measuring oxy- oxypurines were determined by reversed-phase purines, and have discussed adequate sample prep HPLC ultraviolet detection. We used double ƒÊ Bondapak C18 analytical columns in series Accepted July 7, 1994 60 Japanese Journal of Nephrology Vol. 36, No. 11, 1994 Renal handling of oxypurines 1269 (3.9•~300mm, Waters Associates Inc., Milford, MA, USA) for HPLC. We previously demon strated sufficient quantitative recoveries and adequate separations of these compounds with our HPLC method [10, 11]. Plasma and urinary creati nine were determined by an automated modifi cation of the Jaffe reaction. Plasma samples were immediately separated from the formed elements of the blood, stored at -20•Ž and analyzed within three days. Urinary samples were also stored at -20•Ž and analyzed within three days . Fig. 1. Protocol of the drug loading test . Columns represent one-hour urine collections and the Drug Loading Tests arrows indicate when the blood samples•@ were A group of 12 healthy men (23•}2 yrs) was drawn. For at least four days prior to the study , subdivided into three groups of 4 men each. The all subjects had severely restricted purine three groups were similar in terms of age, general intakes and were asked to refrain from strenu level of obesity (estimated by body mass index), ous physical activity. P=plasma; U=urine. alcohol intake, and estimate of work. In all cases, informed consent was obtained and the study was carried out according to the Declaration of follows: Helsinki. The subjects received a low purine diet for four days preceding the test. The prohibited foods and beverages that might affect purine and pyrimidine metabolites were described elsewhere Results [11] and the total caloric intake was set at about 2200kcal/day. The three groups then received Tables 1-3 summarize the results of the loading loading doses of Bb, Pb, and PZA (100mg, 1.5g, tests of Bb, PZA, and Pb, respectively, in healthy 3g, respectively). The tests were performed in the subjects and in two hypouricemic patients. The FE early morning after an overnight fast. The frac changes for each substance before and after drug tional excretion (FE) of UA and the oxypurines administration are shown in Figs. 2-4. The results was calculated for each one-hour interval up to six at baseline, two to three and three to four hours hours after the start of the test. Two hours from after drug administration were used because all the start of the test, the drugs were administered maximum uricosuric and antiuricosuric responses orally (Fig. 1). Urine samples were collected by were obtained two hours after the administration. voiding with a urine flow rate of 2ml/min ensured by oral hydration. Blood samples were collected in Effect of Benzbromarone, Probenecid, and heparinized tubes at the midpoint of each clearance Pyrazinamide on Urate Excretion period. The mean of the levels determined by the Figure 2 illustrates the effects of Bb, Pb, and two clearance periods preceding the drug adminis PZA administration on the FE of UA in four tration was used as the baseline FE value for each healthy subjects and two patients with idiopathic substance. Changes in the FE of UA and the renal hypouricemia. In healthy subjects, Bb pro oxypurines were measured for the four one-hour duced a strong uricosuric effect at two to four hours intervals following drug administration, and the after drug administration, causing the mean FE of increase or decrease in the excretion rate relative UA to increase by more than 400% of the mean to the baseline value was calculated for each test. baseline value. In one patient with hypouricemia, In addition, 100mg of Bb and 3g of PZA were the increase in FE of UA followed the same pattern administered orally to two patients with idiopathic as in healthy subjects, but was less marked. There hypouricemia, and the FE of UA and the oxy was no response on FE of UA in the other patient. purines were evaluated as described above. Pb also produced a marked increase in FE of UA The FE of each substance was calculated as by more than 300% at two to four hours after drug Japanese Journal of Nephrology Vol. 36, No . 11, 1994 61 FE=•¬ 1270 Kinya Hiroshige, et al. Table 1. Results of benzbromarone loading test in four healthy subjects and two hypouricemic patients. Baseline values were calculated by the average of the values from two consecutive predrug urine collections. Results of the control period and at two to three hours and three to four hours after benzbromarone administration are shown. Ccr=creatinine clearance; pUA=plasma concentration of uric acid; pHx=plasma concentration of hypoxanthine; CHx=clearance of hypoxanthine; pX=plasma concentration of xanthine; CX=clearance of xanthine. administration in healthy subjects. The antiurico subjects, whereas the declines in Hx excretion in suric response produced by PZA was almost com the presence of hypouricemia were distinctly lower plete in the healthy subjects, causing urinary UA than those of healthy subjects. excretion to decrease by more than 98% of the baseline value, but it produced no reduction of UA Effect of Benzbromarone, Probenecid, and excretion in two patients with hypouricemia. Pyrazinamide on Xanthine Excretion Figure 4 shows the effects of the drugs on the Effect of Benzbromarone, Probenecid, and FE of X. Bb had no distinct effects in either Pyrazinamide on Hypoxanthine Excretion healthy or hypouricemic subjects within the exper The alterations in FE of Hx following drug imental period. Pb also had no effect in healthy administration are shown in Fig. 3. Bb had no subjects. PZA diminished the FE of X to about distinct effects on the FE of Hx in either healthy or 64% at three to four hours in healthy subjects, hypouricemic subjects. Pb also had no obvious but had markedly fewer effects in hypouricemic effects on the FE of Hx in healthy subjects. PZA patients. diminished the FE of Hx to about 24% at three to four hours after drug administration in healthy 62 Japanese Journal of Nephrology Vol. 36, No. 11, 1994 Renal handling of oxypurines 1271 Table 2. Results of Pyrazinamide loading test in four healthy subjects and two hypouncemic patients . Baseline values were calculated by the average of the values from two consecutive predrug urine collections. Results of the control period and at two to three hours and three to four hours after pyrazinamide administration are shown. Ccr=creatinine clearance; pUA=plasma concentration of uric acid; plx=plasma concentration of hypoxanthine; CHx=clearance of hypoxanthine; pX=plasma concentration of xanthine; CX=clearance of xanthine.