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It Post Date: Sun, 12 Oct 2008 7:26:02 +0000 Present concepts have been reviewed by Mudge and associates (1973) and Weiner (1973).Pharmacological Considerations. It isgenerally believed that the substance to be transported must be incorporated into some form of carrier complex in or near the cell membrane and subsequently released at the opposite pole. Autor of the post: Undefined Simple diffu-sion is often invoked Post Date: Sun, 12 Oct 2008 7:07:32 +0000 This sequence requires energy for the reactivation of the carrier in order to continue. Thus, the primary component of the carrier mechanism would be located at the luminal membrane in the case of active reabsorption and at the peritubular mem-brane in the case of secretion. Simple diffu-sion is often invoked to account for the re-mainder of the journey into the peritubular or luminal fluid. Autor of the post: Undefined There are many conceivable mechanisms Post Date: Sun, 12 Oct 2008 6:53:48 +0000 However, study of the transport of PSP in isolated renal tissue sug-gests that there may be more than one criti-cal step in the transport of some substances (Forster and Hong, 1958). That this is true of other actively transported substances has been amply confirmed.There are many conceivable mechanisms by which the intricate process of renal tubu-lar transport of organic compounds could be depressed. Autor of the post: Undefined The capacity of the tubule Post Date: Sun, 12 Oct 2008 6:34:31 +0000 The least selective would be to interfere with those reactions that supply energy for transport. A more specific ap-proach is that of competitive inhibition. The capacity of the tubule to transport any one of these organic substances is limited and is termed the "transport maximum" (Tm). Autor of the post: Undefined Penicillin PAHLet us designate the substance Post Date: Sun, 12 Oct 2008 6:22:52 +0000 It was appreciated early that the aforemen-tioned acids share a common excretory path-way, since the presence of one reduces the Tm of the other. This is believed to be due to competition for an essential intermediary in the transport system.Penicillin PAHLet us designate the substance that forms the hypothetical complex with organic acids essential for their transport as "X. Autor of the post: Undefined Actually, PAH does reduce Post Date: Sun, 12 Oct 2008 6:04:31 +0000 " Obviously, one limiting factor in this reaction is the supply of activated X (—X) or the rate at which it can be reformed. If PAH and penicillin had similar association and dissociation rates with the carrier X, they would share the transport system and the Tm of each would be halved if both were present in equally high concentrations. Actually, PAH does reduce the tubular secretion of penicillin and was once employed for this purpose. Autor of the post: Undefined The reaction could be depicted Post Date: Sun, 12 Oct 2008 5:50:34 +0000 A commonly en-countered effect of this type results from the use of diuretics (ethacrynic acid, furosemide, and the thi-azides) that compete with uric acid for secretory transport and thus can cause uric acid retention.Suppose, however, that an organic acid had a high affinity for the substance X, combined with it, but subsequently did not dissociate readily. The reaction could be depicted as follows:RCOOH•XRCOOH + XSuch a compound would exist in the tubular cell primarily as the complex, RCOOH • X, and would effectively block the transport of penicillin and yet not be excreted. Autor of the post: Undefined , 1960) Post Date: Sun, 12 Oct 2008 5:33:04 +0000 Probenecid appeared to be an or-ganic acid of this type, since its administration causes prolonged blockade of penicillin secretion and since little probenecid appears in the urine. It has now been shown that probenecid does indeed have a high affinity for the carrier system, and that it is also readily secreted but that subsequently it is re-absorbed by back diffusion (Weiner et a!., 1960). Autor of the post: Undefined Probenecid was developed Post Date: Sun, 12 Oct 2008 5:20:45 +0000 The return of the active inhibitor for recirculation ac-counts for the prolonged action.PROBENECIDHistory. Probenecid was developed as a result of a planned pharmacological approach to achieve a specific objective. Autor of the post: Undefined For this reason, Beyer Post Date: Sun, 12 Oct 2008 5:10:44 +0000 When penicillin was first intro-duced into therapy, the antibiotic was expensive and in short supply. The very rapid renal excretion of the antibiotic was of practical significance. For this reason, Beyer and associates began a systematic study to find an organic acid that would depress the renal tubular secretion of penicillin in the manner described above. 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