Renal excretion of a slauretic-uricosuric agent (MK-196) and interaction with a urate-retaining drug, pyrazinoate, in the chimpanzee.
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.
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D004231:Diuresis / Q000187:drug effects; D004347:Drug Interactions; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007189:Indans / Q000097:blood / Q000494:pharmacology / Q000652:urine*; D007192:Indenes / Q000652:urine*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D002679:Pan troglodytes / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D011718:Pyrazinamide / Q000031:analogs & derivatives; D011719:Pyrazines / Q000494:pharmacology*; D012965:Sodium Chloride / Q000652:urine*; D013997:Time Factors; D014527:Uric Acid / Q000378:metabolism*; D014528:Uricosuric Agents / Q000097:blood / Q000494:pharmacology / Q000652:urine*; D010130:p-Aminohippuric Acid / Q000494:pharmacology
D007189:Indans; D007192:Indenes; D011719:Pyrazines; D014528:Uricosuric Agents; D014527:Uric Acid; D011718:Pyrazinamide; C005296:pyrazinoic acid; D012965:Sodium Chloride; D000086:Acetazolamide; D011339:Probenecid; D010130:p-Aminohippuric Acid