SEARCH · PubMed Health

Results for “AMINOHIPPURIC ACID”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 775 records · Page 43Linked to original sources

PubMed1987

Short-term effect of low and high protein intake on renal function in children with renal disease.

The short-term effect of different levels of protein intake on renal function was investigated in 18 children with moderately (51-85 ml/min/1.73 m2 BSA) or severely (9-50 ml/min/1.73 m2 BSA) reduced glomerular filtration rates (GFR). The GFR and effective renal plasma flow (ERPF), estimated as the clearances of respectively inulin and para-aminohippuric acid during uncontrolled (2-2.5 g/kg bw), low (1.2 g/kg bw for 12 days) and high (3-5 g/kg bw for 24 h) protein intake were determined by a standard clearance method employing continuous infusion and spontaneous voiding. There were no significant differences in GFR or ERPF during uncontrolled and low protein intake. During high protein intake the GFR and ERPF increased significantly in patients with GFRs above 50 ml/min/1.73 m2 BSA and ERPFs above 150 ml/min/1.73 m2 BSA. It is concluded that these findings might indicate a functional reserve capacity in children with only moderately reduced renal function.

Adolescent↗

PubMed1988

Renal function and albumin excretion during exercise in children during remission of the minimal change nephrotic syndrome.

Six patients with the minimal change nephrotic syndrome in remission and seven healthy controls were investigated with regard to renal haemodynamics and albumin excretion before, during and after exercise. The glomerular filtration rate and effective renal plasma flow were determined by a standard clearance method, employing continuous infusion of inulin and para-aminohippuric acid. Microalbuminuria was measured by an immunoturbidimetric method. The work load was standardized at 70% of the maximal working capacity and was applied for 20 min. During exercise there was a significant fall in the glomerular filtration rate and effective renal plasma flow and a significant rise in the filtration fraction. The pattern of renal haemodynamic changes did not differ between the groups. Nor was there any statistically significant difference in urinary albumin excretion, although the exercise-induced increase in albumin excretion of the controls did not reach statistical significance. It is concluded that the renal haemodynamics and urinary albumin excretion of children having long remissions of the minimal change nephrotic syndrome are normal at rest as well as during and after a submaximal exercise test.

Adolescent↗

PubMed1994

Effect of hydrochlorothiazide and indomethacin treatment on renal function in nephrogenic diabetes insipidus.

The purpose of this study was to investigate the effects of treatment with hydrochlorothiazide and hydrochlorothiazide and indomethacin combined on renal function in four boys, two with nephrogenic diabetes insipidus and two with partial nephrogenic diabetes insipidus using the clearances of inulin and para-aminohippuric acid under water diuresis and lithium clearance. Hydrochlorothiazide reduced urine flow and lithium clearance. These effects were further potentiated by addition of indomethacin. No consistent effects on renal plasma flow or glomerular filtration rate were found. It is concluded that treatment with hydrochlorothiazide alone and hydrochlorothiazide and indomethacin combined reduces urine flow in nephrogenic diabetes insipidus by increasing proximal tubular reabsorption of sodium.

Child↗

PubMed1992

Splanchnic and renal vasoconstrictor and metabolic responses to neuropeptide Y in resting and exercising man.

The local clearance of neuropeptide Y (NPY) and whether NPY influences splanchnic and renal metabolism in man have not been investigated previously. The influence of NPY on splanchnic and renal blood flows at physiologically elevated levels has also not been investigated. The effects of a 40-min constant NPY infusion (3 pmol kg-1 min-1) at rest and during 130 min of exercise (50% of VO2max) were studied in six healthy subjects and compared with resting and exercising subjects receiving no NPY. Blood samples were drawn from arterial, hepatic and renal vein catheters for the determination of blood flows (indicators: cardiogreen and para-aminohippuric acid [PAH]), NPY, catecholamines, glucose, lactate and glycerol. NPY infusion was accompanied by: (1) significant fractional extraction of NPY-like immunoreactivity (NPY-Li) by splanchnic tissues at rest (58 +/- 5%) and during exercise (53 +/- 6%), while no arterial-venous differences could be detected across the kidney; (2) a reduction in splanchnic and renal blood flows of up to 18 and 13% respectively (P less than 0.01-0.001) at rest without any additional changes during exercise; and (3) metabolic changes as reflected in: (a) a more marked fall in arterial glucose during exercise compared to the reference group (P less than 0.05); (b) a 35% lower splanchnic glucose release (P less than 0.01) during exercise due to diminished glycogenolysis (P less than 0.01); and (c) a lower arterial lactate level (18% P less than 0.05) together with unchanged splanchnic lactate uptake during exercise, suggesting reduced lactate production by extrahepatic tissues. The disappearance of plasma NPY-Li after the infusions was biphasic with two similar half-lives at rest (4 and 39 min) and during exercise (3 and 43 min).

Adult↗

PubMed1984

Perinatal development of tubular function in the pig.

Renal tubular function has been studied in pig fetuses of 105-112 d gestational age in new-born pigs 5-9 d old. The experiments were performed on anaesthetized animals, urines being collected by inserting a catheter into one ureter of the animal under study. The glomerular filtration rate was estimated and plasma concentrations and urinary excretion of the following substances were measured: sodium, potassium, calcium, ammonia, urea, phosphate, glucose fructose, creatinine, protein and exogenous 4-aminohippuric acid, and inulin. The reabsorption of water was considered in relation to the plasma vasopressin values. New-born pigs were loaded with glucose and fructose in order to determine the maximal tubular transport rate of these substances. Significant changes at birth occur in only a few functions of the tubulus system. Following delivery, major changes are: (1) the increased reabsorption of sodium and water which is probably the most important adaptation to extra-uterine life; (2) an apparent increasing impermeability of the tubular epithelium for creatinine, and (3) the direction of transport of fructose, which is reabsorbed by fetuses whereas neonates demonstrate a net secretion. Glucose and fructose are transported by different mechanisms. The experiments with fructose-loaded piglets demonstrate that there are at least two transport mechanisms for fructose: reabsorption - either passive or active - and secretion. The factors causing a shifting from one mechanism to the other are not yet known.

Absorption↗

PubMed1986

Measurement of blood flow and lipolysis in the hindquarter tissues of the fat-tailed sheep in vivo.

Karakul and Namaqua-Afrikander sheep, both of which are fat-tailed breeds, were examined for suitability as models for studying lipid metabolism in vivo. The anatomy of the blood supply to the hindquarters of both breeds was examined, and a technique developed for sampling the venous outflow from the fat tail. The composition of the tail and the rest of the hindquarters was determined and found to be similar in both breeds. The hindquarters contained 35% fat, about half of which was located in the tail (72-74% fat). Rates of blood flow through the whole hindquarters, tail adipose tissue and leg muscle of Karakul ewes were measured. Tritiated water (TOH) was used for measurement of specific blood flow and p-aminohippuric acid (PAH) for measurement of absolute blood flow. The specific blood flow rate for tail adipose tissue was 3.62 +/- 0.12 ml X min-1 X 100 g-1 and absolute blood flow was estimated as 74 +/- 7 ml X min-1. The absolute flow through the rest of the adipose tissue in the hindquarters was similar to that flowing through the tail, and together they represented about 15% of the total absolute flow through the whole hindquarters, 794 +/- 131 ml X min-1, measured directly using PAH. Total blood flow through the hindquarters estimated from the specific flow rate (using (TOH) and the mass of the hindquarters was 761 +/- 50 ml X min-1. The absolute blood flow through the hindquarters of Namaqua-Afrikander ewes (626 +/- 39 ml X min-1) was lower than that measured in the Karakul ewes, but the difference was not significant (P greater than 0.10). The rates of net release from tail adipose tissue of Karakul ewes measured in vivo were 3.0 +/- 0.6 and 2.0 +/- 0.2 mumol X min-1 X 100 g-1 for free fatty acids and glycerol respectively. Intravenous infusion of noradrenaline (2 micrograms X min-1 X kg-1 liveweight) increased venoarterial differences of both free fatty acids and glycerol 2- to 3-fold and blood flow increased by about 60%. As a result, in response to noradrenaline, net releases for both free fatty acids and glycerol increased 4-fold.

Animals↗

PubMed1967

The influence of the polar anastomotic vessels on autoregulation and the urinary excretion of water and sodium by perfused cat kidneys.

1. Cat kidneys have been perfused from pump-oxygenator and from heart-lung circuits.2. Kidneys perfused from the pump-oxygenator circuit excreted more water and sodium and showed higher values for sodium: potassium in urine than kidneys perfused from heart-lung circuits. Renal plasma flow and the clearances of creatinine and p-aminohippuric acid were similar for preparations perfused by the two different methods.3. Dorsal and ventral polar anastomotic vessels appeared to communicate directly with sheaves of vasa recta in the kidneys of young cats through interlobar vessels.4. Ligature of these polar anastomotic vessels impaired autoregulation of blood flow in perfused cat kidneys.5. Open drainage from these polar vessels during perfusion increased the rates of excretion of water and sodium.6. Histological preparations made from kidneys perfused from pump-oxygenator and from heart-lung circuits for periods of 5-6(1/2) hr showed that the nephrons remain undamaged. The diameters of the tubules correlated with the rates of urine flow immediately before fixation.

Journal Article↗

PubMed1967

Effects of changes in pO2, pCO2 and pH on the total vascular resistance of perfused cat kidneys.

1. The effects of change in arterial P(O2), P(CO2) and pH on the total vascular resistance (RVR) of the perfused cat kidney have been separately measured and expressed as +/- percentage deviations from control values.2. Control levels in arterial blood were pH 7.38, P(-) (O2) 160 mm Hg, in equilibrium with 5% CO(2).3. Increase in P(O2) alone, in excess of 220 mm Hg, raised RVR reversibly reading 108% control levels at a P(O2) 280 mm Hg (P = < 0.001).4. High levels of P(O2) favoured the onset of ;outflow block', which was characterized by irreversible increase in RVR accompanied by rise in plasma filtration fraction (F.F.) and in the extraction ratio for p-aminohippuric acid (PAH extraction).5. Reduction in P(O2) to 80 mm Hg decreased RVR by 4% (P = < 0.001).6. RVR was not significantly affected by pH changes within the range 7.25-7.45. Lowering arterial pH to 7.15 raised RVR by 4% (P = < 0.001) reversibly. Increase in arterial pH to 7.56 raised RVR by 6% (P = < 0.001) reversibly.7. Changes in arterial P(CO2) produced large inverse reversible changes in RVR. Halving P(CO2) raised RVR by 18%; doubling P(CO2) decreased RVR by 25%.8. Changes in RVR caused by alteration of arterial pH or P(CO2) were not accompanied by changes either in F.F. or in PAH extraction.

Acid-Base Equilibrium↗

PubMed1983

Furosemide fails to alter plasma active or inactive renin in conscious sheep but does so in anaesthetized animals.

Regulation of plasma levels of active and inactive renin was investigated using sheep with indwelling artery, vein and bladder catheters. Control and experimental studies were carried out in the same animals on different days. Volume depletion during any single experiment was limited to a maximum of 50 ml. Despite large changes in sodium and water excretion, the diuretic furosemide at two dose levels, 1 and 10 mg/kg, failed to alter plasma levels of either active or inactive renin in conscious sheep. Induction of pentobarbitone anaesthesia in the sheep did not, per se, alter either plasma active or inactive renin. Furosemide (10 mg/kg) in anaesthetized animals produced a similar diuresis and natriuresis response to conscious sheep, but plasma active renin increased by 270% and inactive renin decreased to zero. In conscious sheep given an infusion of papaverine, furosemide also produced an increase in plasma active renin and a concurrent decrease in the inactive form. In both anaesthetized animals and in conscious sheep infused with papaverine, furosemide-induced intrarenal vasodilation, as evidenced by changes in clearance of p-aminohippuric acid, was much reduced in comparison to the conscious animals. This may be significant in relation to the control of renin secretion. It appears that the macula densa sodium receptor, which is considered to regulate renin release, will only function after it has been primed by other intra- or extrarenal factors. This is discussed, particularly in relation to the possible role played by the prostaglandin system.

Anesthesia, Intravenous↗

PubMed2006

Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters.

Amoxicillin and cefaclor are two of the widely used beta-lactam antibiotics in the treatment of urinary tract infections. Both drugs are eliminated mainly by the kidney and rely on renal excretion to exert their antibacterial activities in the urinary tract. Previous studies have suggested the involvement of organic anion and oligopeptide transporters in membrane transport of beta-lactams. The objective of the current study was to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters human organic anion transporter 1 (hOAT1), human peptide transporter 1 (hPepT1), and human peptide transporter 2 (hPepT2) in detail, both as substrates and as inhibitors. Using fluorescence protein tagging and cell sorting, we established Madin-Darby canine kidney cell lines stably expressing highly functional hOAT1, hPepT1, and hPepT2. Amoxicillin and cefaclor inhibited hOAT1-mediated [(3)H]para-aminohippuric acid uptake (K(i) = 11.0 and 1.15 mM, respectively). However, our uptake study revealed that neither drug was transported by hOAT1. Amoxicillin and cefaclor competitively inhibited hPepT2-mediated [(3)H]glycylsarcosine uptake (K(i) = 733 and 65 muM, respectively), whereas much lower affinity for hPepT1 was observed with both antibiotics. Direct uptake studies demonstrated that amoxicillin and cefaclor were transported by hPepT1 and hPepT2. Kinetic analysis showed that hPepT2-mediated uptake of both drugs was saturable with K(m) of 1.04 mM for amoxicillin and 70.2 muM for cefaclor. hPepT2, and to a lesser extent hPepT1, may play an important role in apical transport of amoxicillin and cefaclor in the renal tubule. hOAT1, in contrast, is not involved in basolateral uptake of these antibiotics.

Amoxicillin↗

PubMed2004

Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOat3): further substrate specificity of mOat3.

Organic anion transporter 3 [Oat3(Slc22a8)] plays an important role in the renal handling of organic compounds. The substrate specificity of rat Oat3 and human Oat3 has been elucidated; information on mouse Oat3 (mOat3) is less defined. The aim of this study was to extend the substrate selectivity of mOat3. When expressed in Xenopus laevis oocytes, mOat3 mediated the uptake of p-aminohippuric acid and estron sulfate (ES). In addition to these substrates, we found that several organic compounds such as prostaglandin E(2), prostaglandin F(2alpha), allopurinol, 6-mercaptopurine (6-MP), 5-fluorouracil (5-FU), and l-carnitine are substrates of mOat3, compounds identified for the first time. The apparent K(m) values for the uptake of mOat3 that mediated the transport of 6-MP, 5-FU, and l-carnitine were 4.01 +/- 0.7 microM, 53.9 +/- 8.9 nM, and 61.9 +/- 1.1 nM, respectively. Northern blot analysis revealed that gene coding for mOat3 is predominant in the kidney and, to a lesser extent, in the brain and the eye. Our findings thus provide further insights into the role of Oat3 in renal drug transport.

Allopurinol↗

PubMed2004

Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier.

The "reduced in osteosclerosis" transporter (Roct), which shows decreased expression in the osteosclerosis (oc) mutant mouse, has high homology with rat and human organic anion transporter 3 (OAT3). However, its transport properties and involvement in bone turnover are poorly understood. Here, we examined Roct-mediated transport using a Xenopus laevis oocyte expression system. Roct-expressing oocytes exhibited uptake of [(3)H]estrone sulfate, [(3)H]p-aminohippuric acid, [(3)H]benzylpenicillin, [(3)H]estradiol 17beta-glucronide, [(3)H]indoxyl sulfate, [(14)C]indomethacin, [(3)H]homovanillic acid, [(3)H]cimetidine, [(14)C]glutarate, [(14)C]salicylic acid, and [(3)H]methotrexate. Furthermore, the uptake of [(3)H]benzylpenicillin by Roct coexpressed with Na(+)-dicarboxylate cotransporter was trans-stimulated by glutarate preloading, and [(3)H]estrone sulfate uptake showed a similar tendency, suggesting that Roct is a dicarboxylate exchanger. [(3)H]Benzylpenicillin uptake by Roct was inhibited by OAT3 substrates and inhibitors, and by sulfate or glucuronide conjugates, and compounds involved in bone turnover. Roct mRNA is expressed abundantly in the kidney and was also detected in the brain, choroid plexus, and eye. Immunohistochemical analysis revealed that Roct is localized in brain capillary endothelial cells. These results indicate that the transport properties and tissue distribution of Roct are similar to those of OAT3, suggesting that Roct functions as mouse OAT3. Because Roct is expressed in the kidney and at the blood-brain barrier, it may play a role in the excretion of substrates such as conjugates and bone turnover factors.

Animals↗

PubMed2005

Functional analysis of organic cation transporter 3 expressed in human placenta.

The aim of this study is to investigate the placental transport mechanism of cationic compounds by comparison of the uptake of an organic cation into human placental basal membrane vesicles (BLMVs) with that into organic cation transporter 3 (OCT3)-expressing cells. Reverse transcription-polymerase chain reaction analysis demonstrated that OCT3 is the only OCT isoform expressed in the human placenta. The function of OCT3 was investigated by measuring the uptake of 1-methyl-4-phenylpyridinium (MPP(+)) into human embryonic kidney (HEK)293 cells stably expressing OCT3 (HEK/OCT3 cells). The OCT3-mediated uptake of MPP(+) was sodium- and chloride-independent and saturable, with a Michaelis constant (K(m)) of 82.5 microM. The OCT3-mediated uptake was inhibited by various cationic drugs in a concentration-dependent manner but not by anionic compounds, such as p-aminohippuric acid and captopril, or a zwitterion, carnitine. Western blotting analysis of membrane vesicles prepared from human term placenta revealed that OCT3 is expressed only in BLMVs but not in microvillous membrane vesicles. The uptake of MPP(+) into BLMVs was membrane potential-dependent and saturable, with a K(m) value of 51.8 muM, which is similar to that in HEK293/OCT3 cells. The inhibitory spectrum of various compounds on MPP(+) uptake by BLMVs was also similar to that in HEK293/OCT3 cells. These results suggest that OCT3 is expressed on the basal membrane of human trophoblast cells and plays an important role in the placental transport of cationic compounds.

Adult↗

PubMed2003

In vitro study of the functional expression of organic anion transporting polypeptide 3 at rat choroid plexus epithelial cells and its involvement in the cerebrospinal fluid-to-blood transport of estrone-3-sulfate.

The cerebrospinal fluid-to-blood efflux transport of estrone-3-sulfate (E(1)S) via the blood-cerebrospinal fluid barrier (BCSFB) may play an important role in regulating E(1)S levels in the brain. Here, we investigated the efflux transport of E(1)S at the BCSFB using conditionally immortalized rat choroid plexus epithelial cells (TR-CSFB) and identified the responsible transporter. The [(3)H]E(1)S uptake by TR-CSFB cells was composed of saturable and nonsaturable components, and the K(m) and V(max) values of the saturable component were determined to be 16.8 +/- 5.1 microM and 12.3 +/- 2.3 pmol/min/mg of protein, respectively. [(3)H]E(1)S uptake was inhibited by probenecid, cholate, taurocholate, sulfobromophthalein, dehydroepiandrosterone sulfate, triiodothyronine, thyroxin, and digoxin but not by p-aminohippuric acid, gamma-aminobutyric acid, or methotrexate, suggesting the involvement of organic anion transporting polypeptide (oatp) in the uptake. Reverse transcription-polymerase chain reaction analysis revealed that oatp3 was expressed in TR-CSFB cells and isolated rat choroid plexus, although oatp1 was not detected in either. Xenopus laevis oocytes expressing oatp3 exhibited [(3)H]E(1)S uptake activity with a K(m) of 8.09 +/- 2.83 microM and V(max) of 8.02 +/- 0.87 pmol/h/oocyte. Moreover, oatp3 is localized at the brush-border membrane of choroid plexus epithelial cells. These results suggest that oatp3 is involved in the E(1)S efflux transport at the BCSFB.

Animals↗

PubMed1979

Clinical pharmacokinetics and safety of high doses of ceforanide (BL-S786R) and cefazolin.

The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t((1/2)), 2.8 h), plasma clearance (Cl(p), 48 ml/min per 1.73 m(2)), and renal clearance (Cl(0-12h) (r), 47 ml/min per 1.73 m(2); tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t((1/2)) (1.9 h), area under the plasma concentration-time curve, Cl(r) (60 ml/min per 1.73 m(2); tubular secretion, 80%, and glomerular filtration, 20%), or Cl(p) (75 ml/min per 1.73 m(2)) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 mug/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.

Adult↗

PubMed1986

Autoradiography of tobramycin uptake by the proximal and distal tubules of normal and endotoxin-treated rats.

Multiple factors may modify the pharmacokinetics of aminoglycosides and increase their nephrotoxic potential. In the present study, the influence of Escherichia coli endotoxin on the renal handling of [3H]tobramycin was investigated. The accumulation of [3H]tobramycin in proximal tubules, distal tubules, and collecting ducts was compared in both normal and endotoxin-injected (0.25 mg/kg) rats. Histological observations were also made. Blood pressure and cardiac frequency were recorded, and renal function was evaluated with labeled inulin and p-aminohippuric acid. Following administration of endotoxin, disturbed intrarenal localization of the drug was noted. Grain counts were affected in both proximal and distal tubules. Increased labeling was observed at all time intervals in the proximal tubules. In the distal tubules of endotoxemic animals we could detect higher amounts of drug at 10 and 60 min in the medulla and at 10 min in the cortex. Not all of the tubules were labeled to the same extent. No histological lesion was noted on light microscopy in animals receiving either normal saline or endotoxin. The dose of endotoxin used resulted in very fine physiological disturbance. Both blood pressure and cardiac frequency were minimally affected by endotoxin. Decreases in glomerular filtration rate and renal plasma flow were observed. However, none of these changes was statistically significant. The present study has shown that low doses of endotoxin alter the renal handling of aminoglycosides in the absence of any major physiological disturbance or histological changes. By increasing the total amount of drug within the kidney, endotoxin might increase the nephrotoxic potential of aminoglycosides.

Animals↗

PubMed1987

Mechanism of renal excretion of carumonam in rats, rabbits, dogs, and monkeys.

The mechanism of the renal excretion of carumonam (CRMN) was investigated in rats, rabbits, dogs, and monkeys. Stop-flow analysis in dogs demonstrated that CRMN is exclusively excreted by glomerular filtration. There was no specific CRMN peak corresponding to the peak of p-aminohippuric acid (PAH) secretion or to the trough of Na+-K+ reabsorption in the stop-flow pattern. Although the PAH peak disappeared when probenecid was administered, the CRMN stop-flow pattern showed no change. In rabbits, however, the CRMN concentration peak corresponding with the PAH peak was detected in the stop-flow pattern; the CRMN peak disappeared when probenecid was administered. The pharmacokinetic parameters in plasma, such as the area under the concentration-time curve, the half-life, and the clearance rate, were affected by probenecid in rats, rabbits, and monkeys, but not in dogs. The results suggest that the renal excretion of CRMN in dogs takes place exclusively through glomerular filtration. In rats, rabbits, and monkeys, however, CRMN is excreted through both glomerular filtration and renal tubular secretion.

Animals↗

PubMed1993

Increased renal uptake of gentamicin in endotoxemic rats receiving concomitant thromboxane A2 antagonist therapy.

This report describes the effects of endotoxin and a thromboxane receptor antagonist, L-655,240, on kidney function and the intrarenal pharmacokinetics of aminoglycosides. The rationale for these studies was that thromboxane antagonists may eventually be used in combination with aminoglycosides in patients with gram-negative sepsis and endotoxemia. As aminoglycosides are nephrotoxic and endotoxin has already been shown to increase the renal uptake of gentamicin, we investigated the possibility that thromboxane antagonists might interfere with the nephrotoxic potential of both substances. A decrease in the volume of distribution and an increase in the intracortical concentration of gentamicin were observed in animals given endotoxin. Compared with animals given endotoxin alone, those which received endotoxin plus L-655,240 had significant accumulation of gentamicin in the renal cortex and medulla, as determined by the area under the concentration-time curve, and a significant reduction in the total clearance of the antibiotic (P < 0.05). This difference in uptake could not be attributed to hypotension or changes in the glomerular filtration rate or renal plasma flow. L-655,240 alone did not modify gentamicin pharmacokinetics but did decrease p-aminohippuric acid secretion. Thromboxane antagonists in the context of endotoxemia increase intrarenal uptake of aminoglycosides. If these compounds are to be used as therapeutic agents when endotoxin is present, their influence on renal handling of nephrotoxic drugs needs to be considered. Multiple-dosing regimens deserve investigation.

Animals↗