Effects of SCH27899 (Ziracin), an oligosaccharide everninomicin antibiotic, on urate kinetics in humans.
OBJECTIVE
Intravenous administration of an everninomicin antibiotic, SCH27899 (Ziracin), in healthy subjects caused a marked decrease in serum urate by increasing its urinary excretion, as well as an increase in serum bilirubin in a dose-dependent manner. To clarify the underlying mechanism, a crossover study and an in vitro study were conducted.


METHODS
Crossover study was performed in nine healthy male volunteers over three periods by administering SCH27899 (1-h i.v. infusion of 3 mg/kg) alone, probenecid (2000 mg, p.o.) alone and their combination. Also, an in vitro experiment was conducted using rat brush-border membrane vesicles to elucidate the effect of SCH27899 on urate transport across renal tubular epithelium.


RESULTS
SCH27899 alone and probenecid alone showed a uricosuric, serum urate-lowering effect, and, when given in combination, the effects on serum urate appeared to be additive, as indicated in the earlier phase, prior to the peaks of respective drug effects. Serum and urinary concentrations of SCH27899 were not influenced by the co-administration of probenecid. Serum bilirubin was also significantly increased by both SCH27899 alone and in combination with probenecid. The SCH27899-probenecid combination additive effect on serum bilirubin did not reach significance. SCH27899, probenecid and losartan, an angiotensin-II-receptor antagonist possessing a uricosuric effect, significantly inhibited (14)C-urate uptake into the vesicles, which was dependent on the pH gradient across the membrane; whereas, vancomycin did not.


CONCLUSIONS
It is concluded that SCH27899 itself contributes, at least in part, to a uricosuric effect following i.v. infusion. However, some metabolite(s) may also contribute to this, since the degree of urate-uptake inhibition by SCH27899 was less than probenecid and losartan, and the serum urate-lowering effect was delayed and prolonged compared with the time profile of serum concentration.
Nagashima
Satoru
S
1st Department of Internal Medicine, Hamamatsu University School of Medicine, 431-3192, Hamamatsu, Japan.
Niwa
Masayuki
M
Nishiki
Katsuyuki
K
Hosoya
Tatsuo
T
Hishida
Akira
A
Uematsu
Toshihiko
T
D000328:Adult; D000617:Aminoglycosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001663:Bilirubin / Q000097:blood; D003404:Creatinine / Q000097:blood; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000097:blood*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D014527:Uric Acid; C001202:evernimicin; D003404:Creatinine; D001663:Bilirubin