Naproxen and indomethacin: disposition and effects in the isolated perfused rat kidney.
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Animals↗
Biomedical subjects
F G Russel
Publications and source records attributed to F G Russel.
Renal disposition and effects of naproxen and its l-enantiomer in the isolated perfused rat kidney.
Renal handling, metabolism and effects on kidney function of naproxen and its l-enantiomer were examined in the isolated perfused rat kidney (IPK). Urinary excretion rate of naproxen was much lower than the filtration rate, indicating extensive reabsorption. Naproxen is accumulated considerably in the IPK. This accumulation is concentration-dependent and is probably the result of active secretion of naproxen. Considerable amounts of desmethyl-naproxen were formed in the IPK. The kinetic behavior of the l-enantiomer of naproxen did not differ from naproxen. Addition of 37.5 to 3750 micrograms naproxen caused a decrease in urinary flow, glomerular filtration rate and fractional excretion of sodium, chloride, potassium, magnesium and calcium. The presence of prostaglandin E2 in the perfusate fully opposed the effects of naproxen on kidney function. Addition of 375 micrograms l-enantiomer of naproxen did not influence kidney function. Addition of very high doses (1 x 10(5) micrograms) of naproxen and its l-enantiomer to the IPK caused diuresis and increased the fractional excretion of sodium, chloride, potassium, glucose and calcium. We conclude that the pharmacokinetic behavior and the metabolism of naproxen in the IPK is probably not stereoselective; that relatively low doses of naproxen exert a specific, stereoselective effect on kidney function caused by inhibition of the prostaglandin E2 synthesis and that high doses of naproxen exert a nonstereoselective effect on kidney function.
Animals↗
Solid-phase extraction of furosemide from plasma and urine and subsequent analysis by high-performance liquid chromatography.
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Adult↗
A comparison of three mathematical models to describe the disappearance curves of subcutaneously injected 125I-labelled insulin.
1. The absorption of insulin in constant and varied volumes and concentration was studied in healthy volunteers. 2. Disappearance curves of radioactivity after subcutaneous injection of labelled insulin were fitted with three models: a diffusion rate-limited, a dissolution rate-limited and a capacity-limited model. 3. For each curve and model goodness of fit (r2) and sum of weighted squared deviations (SWSD) were calculated. With constant volume and concentration r2 was greater than 0.097 for each curve. SWSDs with the second model were less than those with the first (NS) and third (P less than 0.01). 4. When volume and concentration were varied, the parameters of the first and third model also varied, arguing against the validity of these models. 5. It is concluded that each of the three models, although yielding an accurate description of the observed data is too simple conceptually. Suggestions for more appropriate modelling are discussed.
Absorption↗
Saturable pharmacokinetics in the renal excretion of drugs.
The renal excretion of drugs is the result of different mechanisms: glomerular filtration, passive back diffusion, tubular secretion and tubular reabsorption. Of these mechanisms the last 2 are saturable, as they involve carrier transport. This also implies that both tubular secretion and tubular reabsorption are susceptible to competition between similar substrates for a common carrier site. Furthermore, transport via these mechanisms is energy-dependent, so-called active transport, able to concentrate a drug. Tubular secretion takes place in the proximal tubule of the nephron. Many organic compounds are actively secreted, but there are separate carrier systems for anions and cations. Anions appear to be transported actively over the basolateral membrane and by a less efficient non-active carrier-mediated process (facilitated diffusion) over the brush border membrane. As a result of these mechanisms, anions tend to accumulate in proximal tubular cells. For cations, however, the active transport step operates over the brush border membrane, whereas the uptake of the cation in the cell occurs via facilitated diffusion over the basolateral membrane. Active reabsorption is most prominent for many nutrients and endogenous substrates (amino acids, glucose, vitamins), but various exogenous compounds also have a certain affinity for the reabsorptive carrier systems. Uricosuric drugs, for instance, interfere with carrier-mediated reabsorption of urate. The occurrence of saturable excretion routes causes dose-dependent, non-linear pharmacokinetics. In clinical pharmacokinetics, tubular secretion can adequately be described with the use of a Michaelis-Menten equation. This implies that a compound undergoing tubular secretion exhibits a concentration-dependent renal clearance. At low plasma concentrations the clearance will be maximal, and for several drugs may be as high as the effective renal plasma flow. Increasing concentrations cause decreasing renal clearance, until eventually the secretion mechanism becomes fully saturated. Then the excretion of the drug in urine will depend primarily on its net rate of filtration. It is important to realise that the non-linear kinetics will be evident from the plasma kinetics only when the saturable pathway contributes to at least some 20% of the total body clearance. Interactions with other substrates, however, are likely to occur even when only a very small amount of drug is transported by the carrier system. Non-linear kinetics inevitably lead to disproportionate accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Drug Interactions↗
Renal handling of indomethacin: isolated membrane vesicles of proximal tubular cells as an in vitro model system for transport.
The indomethacin-transport properties of luminal and contraluminal membrane vesicles derived from dog renal proximal tubular cells were studied. In both membranes saturable sodium gradient-dependent transport of indomethacin, sensitive to probenecid, was observed. In luminal membrane vesicles uptake occurred predominantly by passive facilitated diffusion, whereas in contraluminal membrane vesicles, uptake was based upon both passive simple diffusion and active concentrative transport. As a result, indomethacin may accumulate in vivo in the tubular cells thereby exerting a direct nephrotoxic effect.
Animals↗
Renal handling of salicyluric acid in the isolated perfused rat kidney: evidence for accumulation in tubular cells.
The renal handling of salicyluric acid (SU) was studied over a broad concentration range (0-400 micrograms/ml) in the isolated perfused rat kidney (IPK). The accumulation of SU was determined by difference calculations between the SU dose given and the SU amount present in the perfusate and excreted into the urine. SU accumulates highly in the IPK and this accumulation is concentration-dependent. At low perfusate concentrations (5-20 micrograms/ml) there is a sharp increase in the accumulation (100-400 micrograms/g), whereas at higher concentrations (20-100 micrograms/ml) a small increase (400-500 micrograms/g) is seen. The largest part of the accumulation is probably caused by accumulation of SU in the tubular cells. This is a result of the active uptake of SU over the basolateral membrane followed by facilitated diffusion over the brush-border membrane. As a result of the saturation of the active SU uptake, accumulation reaches a maximal value. Excretion of SU in the IPK involves glomerular filtration, active secretion and reabsorption. Reabsorption is probably a passive process, dependent on the urinary flow and pH. The apparent Michaelis-Menten constant of the excretion is 18.7 +/- 1.8 micrograms/ml and the maximum transport capacity is 69.8 +/- 1.4 micrograms/min. The pharmacokinetic parameters of the excretion of SU were in good agreement with previously reported in vivo values.
Animals↗
Renal clearance of substituted hippurates in the dog. II. 4-Amino-, hydroxy- and methoxy-substituted benzoylglycines.
Plasma kinetics and renal excretion of 4-aminobenzoylglycine (p-aminohippurate), hydroxy- and methoxy-substituted benzoylglycines were studied in three Beagle dogs after rapid i.v. administration of about 1 g. Plasma protein binding of 4-amino-, 3-hydroxy- and 4-hydroxybenzoylglycine was low (less than 15%) and practically constant over a range of 5 to 450 micrograms/ml, whereas the 2-hydroxy analog showed concentration-dependent protein binding (40-80%). The excretory patterns of the 4-amino, 3- and 4-hydroxy analogs were essentially the same; rapid elimination from plasma into urine (greater than 80% of the dose), mainly by very efficient supply-limited tubular secretion. Conversely, the excretion of 2-hydroxybenzoylglycine was characterized by a lower plasma clearance and total renal excretion (64% of the dose), and a limited capacity of the tubular secretory system. The methoxybenzoylglycines showed nonlinear plasma protein binding varying between 10 and 70%, rapid clearance from plasma, largely by renal excretion (72-84% of the administered dose). Tubular secretion of 2- and 3-methoxybenzoylglycine was saturated, whereas complete saturation was not achieved for the 4-methoxy isomer. The kinetic parameters of tubular secretion were estimated with a physiologically based kidney model: 2-hydroxy, tubular transport maximum (TM) = 4.4 +/- 0.9 mg/min, Michael-Menten constant of the tubular secretion mechanism (KT) = 23 +/- 8 micrograms/ml; 2-methoxy-TM = 11.7 +/- 4.9 mg/min, KT = 42 +/- 9 micrograms/ml; 3-methoxy-TM = 8.8 +/- 1.0 mg/mn, KT = 27 +/- 20 micrograms/ml. Inasmuch as secretion of the other compounds was not saturated, only the intrinsic secretion clearance (CLint) = TM/KT could be estimated; 4-amino-CLint = 145 +/- 50 ml/min, 3-hydroxy-CLint = 194 +/- 21 ml/min, 4-hydroxy-CLint = 153 +/- 23 ml/min and 4-methoxy-CLint = 201 +/- 47 ml/min. The 4-methoxy isomer was metabolized to some extent by deconjugation of the glycine moiety and the resulting benzoate was found in plasma but not in urine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Na+ and H+ gradient-dependent transport of p-aminohippurate in membrane vesicles from dog kidney cortex.
The transport of p-aminohippurate (PAH) was studied in basolateral (BLMV) and brush border membrane vesicles (BBMV) isolated from dog kidney cortex. Imposition of an inwardly directed 100 mN Na+ gradient stimulated the uptake of 50 microM [3H]PAH into BLMV, whereas a pH gradient (pHout = 6.0, pHin = 7.4) only slightly enhanced uptake. The Na+ gradient-dependent uptake of PAH was electroneutral, saturable and sensitive to inhibition by probenecid and several anionic drugs, with (apparent) Km = 0.79 +/- 0.16 mM, Vmax = 0.80 +/- 0.05 nmol/mg protein, 15 sec and Ki for probenecid = 0.08 +/- 0.01 mM. Simultaneous imposition of the pH gradient (outward OH- gradient) and inward Na+ gradient stimulated PAH uptake significantly over that with an Na+ gradient alone. These results are consistent with an Na+ gradient-stimulated PAH/OH- exchange mechanism in the basolateral membrane. In BBMV, PAH uptake could be stimulated by an outwardly directed OH- gradient as well as an inward Na+ gradient. Both gradients could drive PAH transport via a mediated probenecid-sensitive pathway. Na+ gradient-stimulated uptake was electrogenic with a (apparent) Km = 4.93 +/- 0.57 mM, Vmax = 6.71 +/- 0.36 nmol/mg protein, 15 sec and Ki,prob = 0.13 +/- 0.01 mM. The kinetic parameters for PAH/OH- exchange were virtually the same, (apparent) Km = 5.72 +/- 0.49 mM, Vmax = 7.87 +/- 0.33 nmol/mg protein, 15 sec and Ki,prob = 0.16 +/- 0.02 mM. When both the Na+ and pH (outward OH-) gradient were simultaneously imposed an almost twofold stimulation in uptake was observed over that with either an Na+ or pH gradient alone. These results suggested that both gradients stimulate PAH transport in BBMV via the same pathway. However, inhibition experiments with various organic anions showed that the specificities of Na+ and pH gradient-stimulated PAH uptake do not entirely overlap. Thus, our results support a simple transport in BBMV, but it cannot be excluded that two separate pathways are involved.
Aminohippuric Acids↗
[The increase in body length of the Dutchman and the attraction of tennis].
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Adult↗
Physiologically based pharmacokinetic model for the renal clearance of phenolsulfonphthalein and the interaction with probenecid and salicyluric acid in the dog.
Plasma kinetics and renal excretion of intravenous phenolsulfonphthalein (PSP, 1.0 g), with and without concomitant administration of probenecid or salicyluric acid (SUA), were studied in the Beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid and SUA. A physiologically based kidney model was developed that incorporates the functional characteristics of the kidney that determine the excretion of PSP, i.e., renal plasma flow, urine flow, nonlinear protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. The interaction with probenecid and SUA could be adequately described with the model by inhibition of the carrier-mediated uptake of PSP into the proximal tubular cells. However, both compounds clearly differed in their inhibitory action. Whereas probenecid showed simple competitive inhibition, for SUA a considerably more complex interaction (two-site competitive system) had to be taken into consideration. Especially in the interaction experiments, only satisfactory fits to the model were obtained when secretion was assumed to be dependent on unbound PSP concentrations. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of PSP within the proximal tubular cells, which was clearly diminished in presence of probenecid or SUA. The predicted accumulation ratios were in good agreement with previous studies.
Animals↗
Quantitative urine collection in renal clearance studies in the dog.
A double-walled urinary catheter is described which allows rapid and quantitative urine collection at short time intervals. The catheter consists of a polyurethane outer cannula in which a small Teflon cannula is inserted. The essential of the catheter is that at the end of a collection period, residual urine in the bladder can be collected completely via the outer cannula by flushing the bladder with physiological salt through the inner cannula. In this manner urine can be collected in a very reproducible way at intervals down to 5 min. The use of the catheter was illustrated in a study on the renal clearance of hippuric acid in the dog. Plasma concentration and renal excretion rate were followed after i.v. injection of 0.9 g sodium hippurate. In accordance with previous studies, it was found that the renal excretion of hippuric acid consisted of glomerular filtration and active tubular secretion. A large variability was observed in the tubular transport maximum (3,800-11,600 micrograms/min) and the Michaelis-Menten constant (22-190 micrograms/ml), which were used to characterize the secretory system. The interpretation and value of these transport parameters is discussed briefly.
Animals↗
Renal clearance of sulphinpyrazone in man.
Six healthy young volunteers received a single dose of sulphinpyrazone 200 mg p.o. Plasma concentration and urinary excretion rate curves showed large intersubject variation for sulphinpyrazone and its metabolites. The sulphide metabolite could only be detected in plasma and not before 3-7 h after ingestion. The total recovery in urine of all compounds varied from 30-56% of the dose. In two subjects the mean residence time of sulphinpyrazone was twice as long as in the other subjects (10.4 h compared with 4.6 h), but the area under the plasma concentration-time curve was comparable to that in the others (mean: 3.0 mg X ml-1 X min), indicating that drug absorption was quantitatively similar but delayed. The renal clearance of sulphinpyrazone varied from 14-40 ml X min-1 (mean: 28 ml X min-1). In view of the very high plasma protein binding of sulphinpyrazone, active tubular secretion is the predominant mechanism in its renal clearance. The same holds for the sulphone metabolite, which has a mean renal clearance of 24 ml X min-1, and even more for the p-hydroxysulphinpyrazone metabolite, which has a renal clearance of 118 ml X min-1. No unambiguous evidence was found in favour of concentration-dependent renal clearance of sulphinpyrazone or its metabolites over the concentration range studied. The renal clearance, especially of sulphinpyrazone, appeared to be dependent on urine pH and not on urine flow rate.
Adult↗
Influence of taurocholate on hepatic clearance and biliary excretion of asialo intestinal alkaline phosphatase in the rat in vivo and in isolated perfused rat liver.
We have used canine intestinal alkaline phosphatase, an asialoglycoprotein, as a tool to study the effect of taurocholate on hepatic asialoglycoprotein transport. After bolus injections of 20 U of alkaline phosphatase into anesthetized rats in vivo and isolated perfused rat livers, a biexponential disappearance pattern was observed; 6.2% of the dose and 0.8% of the dose was excreted in bile, respectively. Taurocholate infusion in vivo and in isolated perfused livers resulted in a virtually complete abolition of the plasma disappearance of alkaline phosphatase in the second slow phase of the curve, whereas the primary disappearance rate was not affected. Wash out experiments showed release of exogenous alkaline phosphatase from the liver, which was strongly increased by taurocholate. Liver perfusion experiments with two subsequent doses of alkaline phosphatase indicated that the taurocholate effect was completely reversible. It is concluded that taurocholate enhances exocytosis of interiorized alkaline phosphatase from liver into plasma. The taurocholate effect on hepatic exocytosis of the asialoglycoprotein may also occur when bile salt concentrations in the systemic or portal circulation, or both, are elevated due to certain liver diseases and postprandial bile salt absorption.
Alkaline Phosphatase↗
Physiologically based pharmacokinetic model for the renal clearance of iodopyracet and the interaction with probenecid in the dog.
Plasma kinetics and renal excretion of iodopyracet (3.0 g, administered i.v.) with and without concomitant administration of probenecid were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid. A physiologically based kidney model is proposed comprising all the functional characteristics of the kidney that determine the excretion of iodopyracet, i.e. renal plasma flow, urine flow, protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. Renal clearance of iodopyracet is characterized by supply-limited elimination at low plasma concentrations and capacity-limited elimination at high plasma levels. The interaction with probenecid could be adequately described with the model by competitive inhibition of the carrier-mediated uptake of iodopyracet into the tubular cells. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of iodopyracet within the cells, which was clearly diminished in the presence of probenecid.
Animals↗
Mechanisms and clinical implications of renal drug excretion.
The body defends itself against potentially harmful compounds like drugs, toxic compounds, and their metabolites by elimination, in which the kidney plays an important role. Renal clearance is used to determine renal elimination mechanisms of a drug, which is the result of glomerular filtration, active tubular secretion and reabsorption. The renal proximal tubule is the primary site of carrier-mediated transport from blood to urine. Renal secretory mechanisms exists for, anionic compounds and organic cations. Both systems comprises several transport proteins, and knowledge of the molecular identity of these transporters and their substrate specificity has increased considerably in the past decade. Due to overlapping specificities of the transport proteins, drug interactions at the level of tubular secretion is an event that may occur in clinical situation. This review describes the different processes that determine renal drug handling, the techniques that have been developed to attain more insight in the various aspects of drug excretion, the functional characteristics of the individual transport proteins, and finally the implications of drug interactions in a clinical perspective.
Animals↗
Renal transport of the glucuronides of paracetamol and p-nitrophenol in the dog.
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Acetaminophen↗
Physiologically based pharmacokinetic model for the renal clearance of salicyluric acid and the interaction with phenolsulfonphthalein in the dog.
Plasma kinetics and renal excretion of salicyluric acid (SUA, 0.8 g) administered iv, with and without concomitant administration of phenolsulfonphthalein (PSP), were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by PSP. A physiologically based kidney model is presented comprising all the functional characteristics of the kidney that determine the excretion of SUA, i.e. renal plasma flow, urine flow, nonlinear protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. The interaction with PSP could be adequately described with the model by noncompetitive inhibition of the carrier-mediated uptake of SUA into the tubular cells. Furthermore, a small but significant reduction in nonrenal SUA clearance was observed. Model calculations showed that, in the control experiments, tubular secretion was accompanied by a pronounced accumulation of SUA within the cells, which was clearly diminished in the presence of PSP. The predicted accumulation ratios were in good agreement with previously reported in vitro values.
Animals↗