Inhibition Of Renal Tubular Secretion Research Articles

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

Probenecid influences transport processes of drugs at several sites in the body and decreases elimination of several quinolones. We sought to explore extent, time course, and mechanism of the interaction between ciprofloxacin and probenecid at renal and nonrenal sites. A randomized, two-way crossover study was conducted in 12 healthy volunteers (in part previously published Clin Pharmacol Ther 1995; 58: 532-41). Subjects received 200 mg ciprofloxacin as 30-min intravenous infusion without and with 3 g probenecid divided into five oral doses. Drug concentrations were analysed by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography. Ciprofloxacin and its 2-aminoethylamino-metabolite (M1) in plasma and urine with and without probenecid were modelled simultaneously with WinNonlin. Data are ratio of geometric means (90% confidence intervals). Addition of probenecid reduced the median renal clearance from 23.8 to 8.25 l h(-1)[65% reduction (59, 71), P < 0.01] for ciprofloxacin and from 20.5 to 8.26 l h(-1) (66% reduction (57, 73), P < 0.01] for M1 (estimated by modelling). Probenecid reduced ciprofloxacin nonrenal clearance by 8% (1, 14) (P < 0.08). Pharmacokinetic modelling indicated competitive inhibition of the renal tubular secretion of ciprofloxacin and M1 by probenecid. The affinity for the renal transporter was 4.4 times higher for ciprofloxacin and 3.6 times higher for M1 than for probenecid, based on the molar ratio. Probenecid did not affect volume of distribution of ciprofloxacin or M1, nonrenal clearance or intercompartmental clearance of ciprofloxacin. Probenecid inhibited the renal tubular secretion of ciprofloxacin and M1, probably by a competitive mechanism and due to reaching >100-fold higher plasma concentrations. Formation of M1, nonrenal clearance and distribution of ciprofloxacin were not affected.

Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated K(m) and Vmax for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an approximately 200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.

Effect on advanced age on p-aminohippurate-induced inhibition of renal tubular secretion in male fischer 344 rats

The effect of aging on glomerular filtration, effective renal plasma flow and on the responsiveness of the renal tubular anion secretory system to inhibition by 4-aminobenzoylglycine ( p-aminohippurate, PAH) was examined in young (5-month) and old (22-month) Fischer 344 male rats. Plasma clearance, protein binding and renal extraction of [ 131I] o-iodohippurate, [ 125I]iothalamate and HPLC-purified [ 99mTc]mercaptoacetyltriglycine (MAG 3), were used as in vivo probes of renal function. The effect of advanced age, without concomitant PAH, on the disposition of these markers was initially determined in ketamine anesthetized, temperature-maintained male rats, ages 5, 14 and 22 months by means of constant infusion clearance studies. Aging per se decreased ( P < 0.05) the kidney-weight normalized or body weight-normalized GFR and effective renal plasma flow rates. GFR values averaged 1.67, 1.43 and 1.32 ml/min per g kidney for the 5-, 14- and 22-month-old rats, respectively. Kidney- or body weight-normalized clearances of MAG 3 and o-iodoh-ippurate showed similar (25–27%) decreases, whereas the absolute values (ml/min) for GFR, o-iodohippurate and MAG 3 clearance rates were not altered by aging. The effective filtration fraction, extraction ratio and plasma protein binding were also unchanged by advanced age. Overall, the age-related decreases in renal function were minimal in Fischer-344 rats, compared to other species. Differences in data normalization, species and gender account, in part, for discrepancies observed when comparing results in different studies on the effects of advanced age on renal function. Subsequently, we examined the effect of aging on the renal responsiveness to inhibition of tubular anion secretion using constant rate PAH infusion studies, adjusted for age-related changes inrenal function. Aging did not alter PAH-induced inhibition of iodohippurate secretion. Inhibition of MAG 3 elimination was more pronounced in the old rats compared to the young controls.

Interaction between allopurinol and pyrazinamide

Pyrazinamide (PZA) is increasingly used with isoniazid and rifampicin, in short-course antituberculous chemotherapy in service programme conditions. Complicating arthralgias occur due to hyperuricaemia induced by the inhibition of renal tubular secretion of uric acid by pyrazinoic acid, the main PZA metabolite. Allopurinol (Al), a hypouricaemic agent, provides no substantial clinical improvement. Pharmacokinetics of PZA and its metabolites were studied in six healthy volunteers, in a cross-over design, after a single oral dose of PZA alone and, in a second trial, after the same dose together with Al. Plasma and urinary concentrations were measured by high pressure liquid chromatography with a column of cation exchange resin. Analysis of the pharmacokinetic parameters showed that Al induced marked changes in levels of PZA metabolites and accumulation of pyrazinoic acid. Despite decreasing uric acid synthesis, allopurinol increased plasma concentrations of pyrazinoic acid, which is directly responsible for the inhibition of renal urate secretion. Other drugs, which do not involve xanthine oxidase inhibition, should be used in the treatment of this side effect of chemotherapy.

Reduction of metformin renal tubular secretion by cimetidine in man.

To determine whether cimetidine altered the renal handling of metformin, seven subjects took 0.25 g metformin daily with and without cimetidine 0.4 g twice daily. Blood and urine samples were collected and assayed for metformin, cimetidine and creatinine by h.p.l.c. Cimetidine significantly increased the area under the plasma metformin concentration-time curve by an average of 50% and reduced its renal clearance over 24 h by 27% (P less than 0.008). There was no alteration in the total urinary recovery of metformin when cimetidine was co-administered. The effect of cimetidine on the renal clearance of metformin was time dependent, being significantly reduced up to 6 h following cimetidine. These results appeared to be consistent with competitive inhibition of renal tubular secretion. Cimetidine had no effect on the renal clearance of creatinine, but time-dependent variations in both metformin and creatinine renal clearance were observed. Metformin had no effect on cimetidine disposition. It is concluded that cimetidine inhibits the renal tubular secretion of metformin in man, resulting in higher circulating plasma concentrations. Because of its propensity for causing dose and concentration-dependent adverse effects, the dose of metformin should be reduced when cimetidine is co-prescribed.

Effect of Probenecid on the Natriuresis and Renin Release Induced by Bumetanide in Man

In a randomized crossover trial in six normal male subjects, the effect of pretreatment with probenecid on natriuresis and renin release in response to bumetanide was studied. The subjects received 120 mEq sodium and 80 mEq potassium per day. A single dose of 2 mg bumetanide was administered on the fourth morning after pretreatment with either placebo or probenecid. Creatinine and uric acid were measured in serum and urine, plasma renin activity was determined by radioimmunoassay of angiotensin I, and plasma and urine concentrations of bumetanide were measured by a highly sensitive radioimmunoassay method. Probenecid reduced both natriuresis and hyperreninemia induced by bumetanide. This effect is postulated to be due not to a direct action on sodium excretion but is probably secondary to inhibition of renal tubular secretion of bumetanide. Consequently, these findings appear to support the concept that the quantity of bumetanide delivered to the tubular lumen is an important determinant of its diuretic effect.

Drug Interactions with Digoxin

Multiple drug administration may affect the actions of digoxin either by altering its myocardial effects (dose-response relationship or pharmacodynamic effect) or by altering the absorption, storage or excretion of the drug (a pharmacokinetic effect). The major pharmacodynamic interactions include potentiation of digitalis toxicity by potassium-wasting diuretics and by succinlycholine. β-Blocking drugs also increase the potential for digoxin to produce adverse sinus or A-V node dysfunction. The pharmacokinetic interactions can be divided into drug interactions which alter digoxin absorption and those which change renal excretion. Estimates of the former are usually based on either steady-state or single dose studies of bioavailability. These studies have demonstrated significant reduction of absorption of oral digoxin by simultaneously administered liquid antacids, cholestyramine, kaolin-pectin, and meals of high fibre content. Reduced digoxin absorption also occurs secondary to therapy with sulphasalazine, para-aminosalicylic acid, and neomycin, probably due to their effect upon gut wall function. Propantheline and diphenoxylate with atropine, which decrease gut motility, increase digoxin absorption, whereas metoclopramide, which increases motility, depresses absorption. The renal excretion of digoxin is not changed importantly by diuretics such as frusemide but is decreased by spironolactone, possibly due to inhibition of renal tubular secretion of digoxin. Quinidine produces dramatic persistent increases in digoxin serum levels, due to decreased renal clearance of the glycoside, without changing the glomerular filtration. In addition to this renal effect, quinidine also seems to decrease the volume of distribution of digoxin, which results in acutely altered digoxin levels even within the first day after quinidine administration. Alteration of the timing of the administration of digoxin from that of a second drug (e.g. as with liquid antacids, kaolin-pectin, or meals of high fibre content), or alteration of the dose of digoxin based on the anticipated change in kinetics (as with spironolactone, quinidine or medications altering gut function or motility), can improve clinical effectiveness of digoxin therapy. However, because of individual variation in the impact of these interactions, routine monitoring of digoxin serum levels is strongly recommended under such circumstances to enhance clinical efficacy and patient safety.

Pharmacokinetics of cefotaxime in normal human volunteers.

The pharmacokinetic parameters of cefotaxime after either intramuscular (Lm.) or intravenous (i.v.) administration were determined in several studies involving about 200 healthy volunteers. In single-dose studies, the pharmacokinetics of cefotaxime appeared to be linear and dose-independent for doses up to 2 g. The mean peak concentration in serum after i.m. injection of 1 g of cefotaxime was ≃22 μg/ml at 0.5 h, whereas the level at 6 h was ≃1.5 μg. After i.v. bolus injection of 1 g of cefotaxime, the mean peak level was ≃105 μg, with an apparent volume of distribution of ≃25 1. After i.v. infusion serum levels ranged from ≃15 μg to ≃40μg, depending on the duration of infusion. Cefotaxime is rapidly eliminated: serum half-life ranged from 0.92 to 1.35 h after 1 g i.m. injection, and from 0.84 to 1.25 h after i.v. injection (terminal phase), the majority of the dose being excreted unchanged in the urine (≃51% within 8 h). Protein binding of cefotaxime ranged from 35 to 45 %. Thus the pharmacokinetic profile of cefotaxime was similar to that reported for cefoxitin, cefamandole and cefuroxime. Co-administration of lignocaine had no significant effect on the absorption and elimination kinetics of cefotaxime while probenecid increased and sustained plasma levels, acting primarily by inhibition of renal tubular secretion. In multiple-dose studies, cefotaxime was administered i.m. and i.v. at different doses, dosing intervals and for periods of 6 to 14 days. There was no evidence that the administration of cefotaxime up to 1 g 6-hourly for 14 days caused any significant accumulation in healthy volunteers.

Clearance of iothalamate-125 I as a measure of glomerular filtration rate in the dog.

ArticleClearance of iothalamate-125 I as a measure of glomerular filtration rate in the dog.J A Gagnon, R W Schrier, T P Weis, W Kokotis, and L U MaillouxJ A Gagnon, R W Schrier, T P Weis, W Kokotis, and L U MaillouxPublished Online:01 May 1971https://doi.org/10.1152/jappl.1971.30.5.774MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByKidneys3 February 2014Kidney Function and DamageSimultaneous technetium-99 MAG3, iodine-131-orthoiodohippurate and iodine-125 iothalamate clearance and biodistribution after bolus injection in rats1 January 2001 | Biopharmaceutics & Drug Disposition, Vol. 21, No. 5[ 51 Cr]EDTA for measuring total and single nephron glomerular filtration rate in the ratActa Physiologica Scandinavica, Vol. 153, No. 3KidneysRadioiodinated Small Molecules and Their ApplicationsEffect on advanced age on p-aminohippurate-induced inhibition of renal tubular secretion in male fischer 344 ratsMechanisms of Ageing and Development, Vol. 56, No. 3Pharmacokinetics of Iothalamate in Endstage Renal Disease8 March 2013 | The Journal of Clinical Pharmacology, Vol. 28, No. 9Renal and non-renal clearances of iothalamateBiopharmaceutics & Drug Disposition, Vol. 7, No. 4Renal tubular accumulation of organic substances: a new in vivo method which differentiates between luminal and peritubular uptakeActa Physiologica Scandinavica, Vol. 123, No. 3KidneysIs 125I iothalamate an ideal marker for glomerular filtration?Kidney International, Vol. 27, No. 1The glomerular filtration rate in unrestrained rabbits determined by means of an implanted telemetrical deviceActa Physiologica Scandinavica, Vol. 117, No. 2Renal radiopharmaceuticals—An updateSeminars in Nuclear Medicine, Vol. 12, No. 3A study of labeled pluronic F-68 after intravenous injection into the dogJournal of Surgical Research, Vol. 25, No. 4The effect of fluorocitrate on urinary calcium and citrate excretionExperientia, Vol. 33, No. 6The preparation of iodine-123 labelled contrast agentsThe International Journal of Applied Radiation and Isotopes, Vol. 25, No. 11-12Radiopharmaceuticals for renal studiesSeminars in Nuclear Medicine, Vol. 4, No. 1Effect of plasma sodium concentration on diluting segment sodium reabsorptionKidney International, Vol. 5, No. 1Kidneys More from this issue > Volume 30Issue 5May 1971Pages 774-8 https://doi.org/10.1152/jappl.1971.30.5.774PubMed5572802History Published online 1 May 1971 Published in print 1 May 1971 Metrics

Single-injection clearances of iothalamate-131-I in the rat.

ARTICLESSingle-injection clearances of iothalamate-131-I in the ratMD Blaufox, and A CohenMD Blaufox, and A CohenPublished Online:01 Feb 1970https://doi.org/10.1152/ajplegacy.1970.218.2.542MoreSectionsPDF (665 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited BypH-Sensitive nanogels based on the electrostatic self-assembly of radionuclide 131 I labeled albumin and carboxymethyl cellulose for synergistic combined chemo-radioisotope therapy of cancer1 January 2018 | Journal of Materials Chemistry B, Vol. 6, No. 29Simultaneous technetium-99 MAG3, iodine-131-orthoiodohippurate and iodine-125 iothalamate clearance and biodistribution after bolus injection in rats1 January 2001 | Biopharmaceutics & Drug Disposition, Vol. 21, No. 5Evaluation of Single-Injection Method of Inulin and Creatinine as a Renal Function Test in Normal Cats.Journal of Veterinary Medical Science, Vol. 60, No. 3A new method of measuring renal function in conscious rats without the use of radioisotopesJournal of Pharmacological and Toxicological Methods, Vol. 36, No. 4Age-dependent enzymuria, proteinuria and changes in renal blood flow and glomerular filtration rate in ratsMechanisms of Ageing and Development, Vol. 82, No. 1Clearance Techniques1 January 2011Rapid measurement of glomerular filtration rate in small animalsKidney International, Vol. 41, No. 2Effect on advanced age on p-aminohippurate-induced inhibition of renal tubular secretion in male fischer 344 ratsMechanisms of Ageing and Development, Vol. 56, No. 3The comparative pharmacokinetics of carboplatin and cisplatin in mice and ratsBiochemical Pharmacology, Vol. 36, No. 12Absorption of iothalamate after oral administration and absorption enhancement by amino acids in dogs and ratsBiopharmaceutics & Drug Disposition, Vol. 7, No. 5The toxicity and teratogenicity of mercuric mercury in the pregnant ratArchives of Toxicology, Vol. 58, No. 4The glomerular filtration rate in unrestrained rabbits determined by means of an implanted telemetrical deviceActa Physiologica Scandinavica, Vol. 117, No. 2Experimental Models and Evaluation of Animal Data for Renal Radiodiagnostic AgentsRenal radiopharmaceuticals—An updateSeminars in Nuclear Medicine, Vol. 12, No. 3The Effects of Salt and Meclofenamate Administration on the Hypertension of Spontaneously Hypertensive Rats3 July 2009 | Clinical and Experimental Hypertension, Vol. 1, No. 3Measurement of renal function with 111In-DTPA in dogsInternational Journal of Nuclear Medicine and Biology, Vol. 4, No. 2Radionuclides in UrologyThe study of renal function in the rat with a gamma cameraInternational Journal of Nuclear Medicine and Biology, Vol. 4, No. 1Radiopharmaceuticals for renal studiesSeminars in Nuclear Medicine, Vol. 4, No. 1Radionuclide clearance techniquesSeminars in Nuclear Medicine, Vol. 4, No. 1Radionuclides in Urology More from this issue > Volume 218Issue 2February 1970Pages 542-544 Copyright & PermissionsCopyright © 1970 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1970.218.2.542PubMed5412472History Published online 1 February 1970 Published in print 1 February 1970 Metrics