Disposition of quinapril and quinaprilat in the isolated perfused rat kidney

Kugler, Alan R.; Olson, Stephen C.; Smith, David Eugene

doi:10.1007/bf02354286

Cited by 10 publications

(19 citation statements)

References 26 publications

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“…With the exception of kidney perfusate pressure (500 M PRO) and FE Na ϩ (5,000 M PRO), physiologic-parameter values for the IPK control, cefdinir alone, and cefdinir-plusinhibitor experiments were similar to each other, consistent with those reported in the literature (2,15,16,19,25,26), and reasonably stable over the entire duration of each experiment. Increased Na ϩ excretion for the high dose of PRO may be related to the elevated concentrations of this organic anion in the renal tubular lumen and peritubular capillaries.…”

Section: Discussionsupporting

confidence: 86%

“…Figure 1 shows a schematic representation of the IPK apparatus, and the operational details have been described elsewhere (15). Briefly, perfusate was pumped from a reservoir and passed through a system of four parallel filters.…”

Section: Animalsmentioning

confidence: 99%

“…We used the IPK model, since it can be subjected to various physiologic, biochemical, or pharmacological alterations in a controlled manner and systemic influences on renal function can largely be eliminated. In addition, specific and precise data on CL R and factors altering renal clearance mechanisms can be readily generated (2,15,16,19,25,26,30). In this regard, the individual contributions of filtration, secretion, reabsorption, and metabolism to the CL R can be determined by the use of competitive and metabolic inhibitors.…”

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confidence: 99%

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Effects of Organic Anion, Organic Cation, and Dipeptide Transport Inhibitors on Cefdinir in the Isolated Perfused Rat Kidney

Lepsy

Guttendorf

Kugler

et al. 2003

Antimicrob Agents Chemother

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Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion.Cefdinir (Omnicef; Abbott Laboratories) is an extendedspectrum third-generation cephalosporin approved for use in the United States, Japan, and several countries in Europe. Prescribed for use in treating mild to moderate bacterial infections in adults, children, and infants, cefdinir demonstrates excellent activity against a wide range of gram-positive and gram-negative bacteria. Cefdinir MICs have been reported to be comparable or superior to those of cephalexin, cefaclor, cefixime, cefpodoxime, cefuroxime, and ceftibuten for group A, B, C, F, and G streptococci, viridans group streptococci, Staphylococcus aureus, and Staphylococcus epidermidis. For Streptococcus pneumoniae, the in vitro activity of cefdinir has been reported to be comparable to those of cefuroxime and cefpodoxime and superior to those of other evaluated cephalosporins. Because of its hydroxyimino functionality, cefdinir is resistant to a broad variety of ␤-lactamases and exhibits a ␤-lactam stability profile generally better than those observed with cefaclor and cefuroxime (9).With respect to pharmacokinetics, cefdinir demonstrates oral bioavailability of ϳ16 to 25%. The drug is widely distributed in the body and is not appreciably metabolized once absorbed (10,20). Cefdinir elimination is primarily...

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Section: Discussionsupporting

confidence: 86%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Organic Anion, Organic Cation, and Dipeptide Transport Inhibitors on Cefdinir in the Isolated Perfused Rat Kidney

Lepsy

Guttendorf

Kugler

et al. 2003

Antimicrob Agents Chemother

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“…For the experimental field of optimizing preservation solutions, small animal models which are of great value for physiological and pharmacological studies [10, 11, 12, 13, 14], exhibited disadvantages such as differences in organ geometry when compared to human conditions. Therefore, the porcine kidney resembled the best approach to investigate perfusion/ischemia-related renal effects [15, 16, 17, 18, 19].…”

Section: Introductionmentioning

confidence: 99%

A Model of Isolated Autologously Hemoperfused Porcine Slaughterhouse Kidneys

Große-Siestrup¹,

Unger²,

Fehrenberg³

et al. 2002

Nephron

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Background: The rapidly evolving field of transplantation research with a focus on ischemic and reperfusion injuries has gained importance since the methodology of organ preservation significantly limits graft survival. Numerous models of isolated perfused kidneys have been established in the past years but limitations such as organ size, perfusate and ethical standards have restricted a widespread research in this area. Methods: A model of hemoperfused isolated porcine slaughterhouse kidneys was established which encompasses the advantages of autologous blood as optimal perfusate and a reduction of animal experiments. Results: The size and geometry of the porcine kidney is more comparable to human conditions and various renal functions, blood parameters and morphology can easily be accessed in the present model. Stable organ function can be maintained over 2 h with an amount of 500–1,000 ml of autologous blood which is metabolically controlled via a dialysis system. Conclusion: In summary, the present model describes a new and economic approach for targeting renal function in transplantation models by combining autologous blood as optimal perfusate with a well-defined organ geometry and function and slaughterhouse animals as a source.

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“…Active tubular secretion is the predominant mediator of its renal clearance . Previous studies in isolated perfused rat kidney have suggested that both quinapril and quinaprilat are actively secreted in proximal tubular cells of the kidney (Kugler et al, 1995). Still, the precise mechanistic basis for renal tubular secretion of quinapril and quinaprilat remains unknown.…”

mentioning

confidence: 98%

Renal Organic Anion Transporter-Mediated Drug-Drug Interaction between Gemcabene and Quinapril

Yuan¹,

Feng²,

Yon³

et al. 2009

J Pharmacol Exp Ther

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In humans and rats, a synergistic blood pressure reduction was observed when the fibrate gemcabene (CI-1027) was coadministered with the angiotensin-converting enzyme inhibitor quinapril. In a quinapril (3 mg/kg) pharmacokinetic rat study, there was a 40% decrease in urinary excretion and a 53% increase in plasma area under the curve from 0 to 24 h of the active metabolite quinaprilat when coadministered with gemcabene (30 mg/kg). This observation revealed a possible transporter-mediated drug-drug interaction (DDI) between gemcabene and quinapril. This led to a series of studies investigating the underlying clearance mechanisms associated with these compounds intended to elucidate renal transporter interactions between quinapril and gemcabene. In vitro transporter studies using human embryonic kidney 293 cells transfected with human or rat organic anion transporter 3 (hOAT3, rOat3) revealed that quinaprilat is a substrate in both species, with a K m value of 13.4 M for hOAT3. Subsequent studies discovered that gemcabene inhibited quinaprilat uptake by hOAT3 and rOat3 at IC 50 values of 35 and 48 M, respectively. Moreover, gemcabene acylglucuronide, the major metabolite of gemcabene glucuronidation, also inhibited hOAT3-and rOat3-mediated uptake of quinaprilat at IC 50 values of 197 and 133 M, respectively. High plasma concentrations of gemcabene (Ͼ100 M) achieved in humans and rats upon oral dosing corroborate with gemcabene inhibition of renal OAT3-mediated secretion of quinaprilat in vitro. This investigation established that a DDI between gemcabene and quinapril involving inhibition of renal transporters and subsequent elevation in plasma concentrations of quinaprilat is responsible for the apparent synergistic blood pressure reduction observed with these compounds.The dialkyl ether dicarboxylic acid gemcabene (CI-1027; Fig. 1) is a representative of a class of lipid-regulating compounds characterized by the presence of a gem-dimethyl carboxylate moiety. Gemcabene advanced into early clinical development as a therapeutic used to increase high-density lipoprotein while lowering serum triglyceride in dyslipidemic patients (Bays and Stein, 2003). Gemcabene exhibited near complete absorption in human and rat and achieved high plasma exposure at therapeutic doses. In rat, 30 mg/kg gemcabene reached a mean C max value of 376 M and decreased low-density lipoprotein and the very-low-density lipoprotein cholesterol by 40 and 75%, respectively (Pfizer, internal data). In humans, low-density lipoprotein was reduced by 25% at a C max value of 884 M with 900 mg once daily administration of gemcabene (Pfizer, internal data). It has been shown clinically that gemcabene is cleared almost exclusively by glucuronidation followed by renal elimination, with 78% of the radioactive dose (61% glucuronide and 17% unchanged parent) recovered in human urine (Pfizer, internal data). UDP-glucuronosyltransferase 2B7 is the major enzyme responsible for gemcabene glucuronidation, with the major metabolite being an acylglucuronide (...

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Disposition of quinapril and quinaprilat in the isolated perfused rat kidney

Cited by 10 publications

References 26 publications

Effects of Organic Anion, Organic Cation, and Dipeptide Transport Inhibitors on Cefdinir in the Isolated Perfused Rat Kidney

Effects of Organic Anion, Organic Cation, and Dipeptide Transport Inhibitors on Cefdinir in the Isolated Perfused Rat Kidney

A Model of Isolated Autologously Hemoperfused Porcine Slaughterhouse Kidneys

Renal Organic Anion Transporter-Mediated Drug-Drug Interaction between Gemcabene and Quinapril

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