Fanelli G M, Bohn D L, Zacchei A G
J Pharmacol Exp Ther. 1977 Feb;200(2):413-9.
The excretory pattern for MK-196 is ocmpatible with that of other weak organic acids such as salicylate and probenecid. Tubular secretion of MK-196 is strongly inhibitied by probenecid and high loads of p-aminohippurate. Urinary excretion of MK-196 is increased 10-fold when the urine is alkaline. Clearances of MK-196 were not corrected for plasma protein binding of the drug which is very high (greater than 99%). Bidirectional transport processes are operative in that MK-196 is secreted by the renal tubule and passively back diffuses across the tubular epithelium by a pH-dependent process. MK-196 is able to overcome pyrazinoate-induced urate retention, whereas probenecid is not when studied by conventional clearance techniques. The uricosuric activity of MK-196 appears to be somewhat less with pyrazinoate than in its absence. When MK-196 is administered prior to pyrazinoate an attenuated uricosuric response was observed. This finding cannot be ascribed to a temporal decline in uricosuric action. Diuresis and saluresis produced by MK-196 are not influenced by pyrazinoate. The interaction of MK=196 and pyrazinoate on urate excretion is in direct contrast to results obtained with probenecid and pyrazinoate. A model has been proposed to explain this unique finding.
MK-196的排泄模式与其他弱有机酸如阿司匹林和丙磺舒的排泄模式相符。丙磺舒和高剂量的对氨基马尿酸可强烈抑制MK-196的肾小管分泌。当尿液呈碱性时，MK-196的尿排泄量增加10倍。未对MK-196的清除率进行药物血浆蛋白结合校正，该药物的血浆蛋白结合率非常高（大于99%）。双向转运过程起作用，因为MK-196由肾小管分泌，并通过pH依赖性过程被动地反向扩散穿过肾小管上皮。通过传统清除技术研究发现，MK-196能够克服吡嗪酸盐诱导的尿酸潴留，而丙磺舒则不能。与无吡嗪酸盐时相比，MK-196在有吡嗪酸盐时的促尿酸尿活性似乎有所降低。当在吡嗪酸盐之前给予MK-196时，观察到促尿酸尿反应减弱。这一发现不能归因于促尿酸尿作用的时间性下降。MK-196产生的利尿和利盐作用不受吡嗪酸盐影响。MK-196与吡嗪酸盐对尿酸排泄的相互作用与丙磺舒和吡嗪酸盐的结果形成直接对比。已提出一个模型来解释这一独特发现。
