Effect of probenecid on the disposition of captopril and captopril dimer in the rat

Drummer, Olaf H.; Thompson, J.; Hooper, Rita; Jarrott, Bevyn

doi:10.1016/0006-2952(85)90356-9

Cited by 11 publications

(5 citation statements)

References 18 publications

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“…Other quinolones have been reported to be transported by both the anionic (7,8,19) and cationic (20) transport systems in humans. The objective of this three-arm, parallel-design study was to identify the active transport system of renal tubular secretion of ofloxacin in rats by using inhibitors of the anionic (probenecid) (3,5,15) and cationic (cimetidine) (3, 23) transport systems.…”

mentioning

confidence: 99%

Effects of Probenecid and Cimetidine on Renal Disposition of Ofloxacin in Rats

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Halstenson

1998

Antimicrob Agents Chemother

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mentioning

confidence: 99%

Effects of Probenecid and Cimetidine on Renal Disposition of Ofloxacin in Rats

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Halstenson

1998

Antimicrob Agents Chemother

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“…Captopril, a marketed angiotensin-converting enzyme inhibitor used primarily as an antihypertensive, demonstrates similar pharmacokinetics where oxidation of the free sulfhydryl group in captopril results in the formation of disulfides conjugates (Yeung et al, 1983;Drummer and Jarrott, 1984;Worland et al, 1984;Drummer et al, 1985). The disulfides of captopril can be reversibly reduced by a combination of enzymatic and redox processes to the monomer.…”

Section: Pharmacokinetics Of E2072 and Its Homodisulfidementioning

confidence: 99%

“…E2072 contains a terminal thiol functional group. Terminal thiols, such as in captopril, have been shown to be reactive both in vivo and in vitro Drummer et al, 1985), with the potential to form disulfide dimers and mixed disulfides with other free thiols upon entering the systemic circulation. Bearing this in mind, the studies presented here were aimed at delineating not only the pharmacokinetics of the parent drug E2072 but also the pharmacokinetics of its homodisulfide, which in preliminary studies was identified in high concentrations in plasma on administration of E2072.…”

Section: Introductionmentioning

confidence: 99%

Reversible Disulfide Formation of the Glutamate Carboxypeptidase II Inhibitor E2072 Results in Prolonged Systemic Exposures In Vivo

et al. 2012

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ABSTRACT:E2072 [(3-2-mercaptoethyl)biphenyl-2,3-dicarboxylic acid] is a novel, potent and selective thiol-based glutamate carboxypeptidase II (GCP-II) inhibitor that has shown robust analgesic and neuroprotective efficacy in preclinical models of neuropathic pain and chemotherapy-induced peripheral neuropathy. For the first time, we describe the drug metabolism and pharmacokinetic profile of E2072 in rodents and primates. Intravenously administered E2072 was found to exhibit an unexpectedly long terminal half-life (105 ؎ 40 h) in rats. The long half-life was found to be the result of its ability to rapidly form reversible homo-and possibly heterodisulfides that served as a continuous E2072 depot. The half-life of reversible homodisulfides was 208 ؎ 81 h. In further support, direct intravenous administration of the E2072-homodisulfide in rats resulted in the formation of E2072, with both E2072 and its disulfide detected in plasma up to 7 days after dose. The observed long exposures were consistent with the sustained efficacy of E2072 in rodent pain models for several days after dose cessation. It is noteworthy that a shorter t 1/2 of E2072 (23.0 ؎ 1.2 h) and its homodisulfide (21.0 ؎ 0.95 h) was observed in primates, indicating interspecies differences in its disposition. In addition, E2072 was found to be orally available with an absolute bioavailability of ϳ30% in rats and ϳ39% in monkeys. A tissue distribution study of E2072 and its homodisulfide in rats showed good tissue penetration, particularly in sciatic nerve, the presumed site of action for treatment of neuropathy. Metabolic stability and the correlation between pharmacokinetic profile and pharmacological efficacy support the use of this GCP-II inhibitor in the clinic.

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“…This active transport results in possible pharmacokinetic interactions with other drugs excreted by the same mechanism (for a review, see reference 12). In particular, some angiotensin-converting enzyme (ACE) inhibitors, which have an oligopeptidic structure, have been shown to be secreted by this transport system (4,7). In a previous study (8), a strong interaction between cephalexin and captopril or quinapril was demonstrated in rats; this interaction resulted in decreased cephalexin clearance by factors of 2.2 (captopril) and 2.7 (quinapril).…”

mentioning

confidence: 99%

“…Indeed, cefdinir glomerular filtration CL or f u ϫ GFR (9) is 0.15 ϫ 10, which is equal to 1.5 ml/min/kg, which is far lower than 5.3 ml/min/kg. Since cefdinir, like many other ␤-lactams, and ACE inhibitors are expected to be secreted by the renal anionic transport system (1,4,5,7,12), inhibition of cefdinir tubular secretion at the carrier level is the most probable mechanism for this pharmacokinetic interaction.…”

mentioning

confidence: 99%

Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats

Jacolot

Tod

Petitjean

1996

Antimicrob Agents Chemother

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The pharmacokinetic interaction between cefdinir and an angiotensin-converting enzyme inhibitor (captopril or quinapril) was investigated in rats. The linearity of cefdinir pharmacokinetics was demonstrated in three groups of rats receiving 10, 20, or 40 mg of cefdinir per kg of body weight intravenously. Then, three other groups of rats were established as follows: group 1 (n = 5) received cefdinir (10 mg/kg) intravenously, and 12 blood samples per rat were drawn between 0 and 8 h after injection of the dose; group 2 (n = 5) was treated in the same way as group 1, but captopril (0.8 mg/kg) was coadministered by intraintestinal injection into all animals; group 3 (n = 6) was treated in the same way as group 2, but quinapril (0.8 mg/kg) replaced captopril. Plasma cefdinir concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method. Finally, three groups of four or five rats each were set up as described above, but the cefdinir dose was 20 mg/kg and the animals were sacrificed 1 h after drug injection to collect blood to determine the unbound cefdinir fraction (fu) by ultrafiltration. The angiotensin-converting enzyme inhibitors increased the mean cefdinir area under the concentration-time curve up to 8 h by a factor of 1.8 (captopril; P < 0.05) and a factor of 3.5 (quinapril; P < 0.05). With captopril, mean cefdinir clearance was decreased by a factor of 2, and the volume of distribution increased by the same factor, while the fu increased from 15.4% +/- 3.0% (cefdinir alone) to 22.8% +/- 10.9% (cefdinir plus captopril). Captopril increased the cefdinir half-life from 0.62 +/- 0.17 to 2.92 +/- 0.95 h. With quinapril, the interaction was so strong that no elimination phase was detectable in four of the six rats, and therefore, no pharmacokinetic parameter values other than the cefdinir fu could be calculated; the cefdinir fu increased to 25.1% +/- 11.1%. It is concluded that captopril and quinapril (and/or their metabolites) have a major impact on the disposition of cefdinir in rats, probably by competition at the plasma protein-binding level and at the tubular anionic carrier level. This latter mechanism should also be relevant in humans.

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Effect of probenecid on the disposition of captopril and captopril dimer in the rat

Cited by 11 publications

References 18 publications

Effects of Probenecid and Cimetidine on Renal Disposition of Ofloxacin in Rats

Effects of Probenecid and Cimetidine on Renal Disposition of Ofloxacin in Rats

Reversible Disulfide Formation of the Glutamate Carboxypeptidase II Inhibitor E2072 Results in Prolonged Systemic Exposures In Vivo

Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats

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