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[The kinetics of sulfamerazine (Mebacid) and the effect of sulfamerazine therapy on p-aminohippuric acid clearance in pregnancy].

Elimination half-life of Sulfamerazin (Mebacid) was not different in pregnant and non-pregnant women after a single oral dose and after 11 days repeated administration in therapeutic dosis. The initial concentrations of Sulfamerazin are lower in pregnants than in non-pregnants. Elimination half-life of p-aminohippurate (PAH) is shortened by Sulfamerazin-pretreatment, renal excretion of PAH is increased respectively.

Adult↗

[Studies on the kinetics of sulfaclomide and the effect of sulfaclomide therapy on p-aminohippuric acid clearance in pregnancy].

After a single oral dose and after 11 day repeated administration of Sulfaclomide elimination half-life of Sulfaclomid was not different in pregnant and in nonpregnant women. The initial serum concentrations of Sulfaclomid are lower in pregnant than in nonpregnant persons. Nearly all Sulfaclomid measurable in serum exists from unchanged sulfonamide. This rate does not change during treatment. By treatment with Sulfaclomid elimination half-life of p-aminohippurate (PAH) is shortened, renal excretion of p-aminohippurate is significant increased.

Aminohippuric Acids↗

Substrate stimulation of para-aminohippuric acid transport: effect on uptake and runout.

The ability of penicillin pretreatment to increase PAH accumulation by slices of newborn rabbit renal cortex was dissected into two components, uptake and runout. The oxygen-requiring component of the uptake process was significantly enhanced by penicillin treatment, whereas runout was unaffected. Kinetically, the data suggest that penicillin alters the affinity of the transport system for PAH. Due to the limitations of such a kinetic analysis, no conclusions may be drawn from such a suggestion. However, it may be concluded that penicillin pretreatment increases renal accumulation of PAH solely by stimulating the uptake process. Elucidation of the molecular changes involved will require techniques more sophisticated than uptake into renal cortical slices.

Age Factors↗

Measurement of glomerular filtration rate and effective renal plasma flow in the conscious beagle dog by single intravenous bolus of iohexol and p-aminohippuric acid.

The objective of this study was to validate a kinetic approach for the simultaneous measurement of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in the dog. Six healthy male Beagle dogs were randomly assigned in a three-period cross-over study of intravenous bolus administration of iohexol (64.7 mg/kg), PAH (10 mg/kg), and an iohexol/PAH mixture. PAH and iohexol were determined simultaneously by a validated high-performance liquid chromatographic method. The iohexol and PAH data obtained after intravenous administration were analyzed using noncompartmental and bicompartmental approaches. A simplified iohexol plasma clearance was also calculated from the terminal elimination phase of the plasma iohexol concentrations versus time profile. The total plasma clearance values for PAH and exo-iohexol were 13+/-2.3 mL/kg/min and 2.9+/-0.3 mL/kg/min, respectively. No significant (or biologically relevant) effect of coadministration of PAH and iohexol was observed on the pharmacokinetic parameters of either drug. The calculation of simplified plasma clearance led to an overestimation of the true plasma clearance. In conclusion, GFR and ERPF can easily and rapidly be measured in the dog by this approach which is relatively noninvasive.

Animals↗

High-performance liquid chromatography of the renal blood flow marker p-aminohippuric acid (PAH) and its metabolite N-acetyl PAH improves PAH clearance measurements.

PAH (N-(4-aminobenzoyl)glycin) clearance measurements have been used for 50 years in clinical research for the determination of renal plasma flow. The quantitation of PAH in plasma or urine is generally performed by colorimetric method after diazotation reaction but the measurements must be corrected for the unspecific residual response observed in blank plasma. We have developed a HPLC method to specifically determine PAH and its metabolite NAc-PAH using a gradient elution ion-pair reversed-phase chromatography with UV detection at 273 and 265 nm, respectively. The separations were performed at room temperature on a ChromCart (125 mmx4 mm I.D.) Nucleosil 100-5 microm C18AB cartridge column, using a gradient elution of MeOH-buffer pH 3.9 1:99-->15:85 over 15 min. The pH 3.9 buffered aqueous solution consisted in a mixture of 375 ml sodium citrate-citric acid solution (21.01 g citric acid and 8.0 g NaOH per liter), added up with 2.7 ml H3PO4 85%, 1.0 g of sodium heptanesulfonate and completed ad 1000 ml with ultrapure water. The N-acetyltransferase activity does not seem to notably affect PAH clearances, although NAc-PAH represents 10.2+/-2.7% of PAH excreted unchanged in 12 healthy subjects. The performance of the HPLC and the colorimetric method have been compared using urine and plasma samples collected from healthy volunteers. Good correlations (r=0.94 and 0.97, for plasma and urine, respectively) are found between the results obtained with both techniques. However, the colorimetric method gives higher concentrations of PAH in urine and lower concentrations in plasma than those determined by HPLC. Hence, both renal (ClR) and systemic (Cls) clearances are systematically higher (35.1 and 17.8%, respectively) with the colorimetric method. The fraction of PAH excreted by the kidney ClR/ClS calculated from HPLC data (n=143) is, as expected, always <1 (mean=0.73+/-0.11), whereas the colorimetric method gives a mean extraction ratio of 0.87+/-0.13 implying some unphysiological values (>1). In conclusion, HPLC not only enables the simultaneous quantitation of PAH and NAc-PAH, but may also provide more accurate and precise PAH clearance measurements.

Biomarkers↗

Renal function and histopathologic changes in children after liver transplantation.

Up to 60% reduction of renal function has been reported after orthotopic liver transplantation (OLT) in patients receiving cyclosporine. We prospectively investigated renal function and histopathology in 16 children on triple immunosuppression therapy during 3 years after OLT. Cyclosporine was administered in 3 doses/day to preschool children. The median age at OLT was 5.4 years. Determinations of chromium 51-labeled ethylenediaminetetraacetic acid, p = aminohippuric acid, lithium, and sodium clearances, measurements of serum and urinary electrolytes, and urinary concentration tests were performed. Renal biopsy specimens were taken 18 and 36 months after transplantation. The mean glomerular filtration rate was 121.5 ml/min per 1.73 m2 before transplantation, 86.3 at discharge, and 119.4 36 months after OLT. Hyperuricemia, hyperkalemia, and reduced urinary concentrating capacity were common. Hyperkalemia occurred in 13% to 19% of the patients, only during the first 6 months. Hyperuricemia and reduced concentrating capacity occurred with incidences of 17% to 44% and 40% to 63%, respectively. Histopathologic changes were mild, and severe nephrotoxic effects of cyclosporine was not seen. However, tubular atrophy, mesangial matrix increase, and mesangial cell proliferation were common. We conclude that triple immunosuppression with cyclosporine administration, in three doses per day, to small children and careful renal follow-up ensure good renal function after OLT.

Adolescent↗

Simultaneous determination of p-aminobenzoic acid and its metabolites in urine by high performance liquid chromatography.

We developed a new HPLC method for the determination of p-aminobenzoic acid (PABA) and its metabolites (p-aminohippuric acid, N-acetyl-p-aminohippuric acid, N-acetyl-p-aminobenzoic acid) in urine. As the internal standard m-hydroxybenzoic acid was used. In the isocratic elution the mobile phase consisted of methanol and 0.02 M ammonium acetate (20:80 v/v, pH 4.0). The separation was carried out on the C18, reversed-phase column, particle size 5 microns. The separated components were detected at 280 nm. The method can be used in the assessment of the response of pancrease (secretion of digestive enzymes) to soya feeding as well as in the diagnosis of the exocrine pancreatic diseases of animals.

4-Aminobenzoic Acid↗

In vitro assessment of cephaloridine nephrotoxicity: comparison of renal cortical slice and renal tubule fragment techniques.

Renal cortical slices and a suspension of renal tubule fragments were prepared from male Wistar rats that had received a single s.c. dose of either cephaloridine (100 mg/kg) or normal saline (1 ml/kg) 48 h previously. The comparative sensitivity of these tissue preparations as in vitro models to assess nephrotoxin-induced changes in renal function was investigated by measuring the ability of the preparations to undertake the active accumulation of [3H]para-aminohippuric acid and to undertake gluconeogenesis from sodium pyruvate. Through the use of the cortical slice technique, [3H]para-aminohippuric acid tissue accumulation and glucose production in the cephaloridine-treated group were not significantly different from control. In contrast, using the tubule fragment technique, significant (p less than 0.05) reductions in the accumulation of [3H]para-aminohippuric acid and in the production of glucose via gluconeogenesis, between cephaloridine and normal saline control treatments were observed. Control values in the tubule fragment technique, for para-aminohippuric acid transport and glucose production via gluconeogenesis, were observed to be much greater than control values obtained from the cortical slice technique. It is suggested that the tubule fragment technique may be a more valuable in vitro preparation to assess the effects of potential nephrotoxins on tubule transport function than the still widely used cortical slice technique. The use of specific metabolic substrates, such as acetate, that will stimulate cellular metabolism and substrate transport, will also enhance the value of the technique.

Aminohippuric Acids↗

Sympathetic influence on transport functions in the choroid plexus of rabbit and rat.

In vitro uptake of an organic base (choline) and an organic acid (p-aminohippuric acid; PAH), both radiolabelled, was measured in isolated choroid plexus of rat and rabbit, and expressed as tissue/medium ratios. A significant increase in the tissue accumulation of choline was seen in denervated rabbit choroid plexus 1 week following unilateral cervical sympathectomy. The accumulation of PAH was not affected. The uptake of both test substances was significantly reduced after sympathetic denervation of the rat choroid plexus. The results agree with the local sympathetic inhibition of cerebrospinal fluid production in rabbit (corresponding studies on rat have not been performed), and favour the assumption that the adrenergic nerves in the choroid plexus mediate direct effects on the plexus epithelium.

Aminohippuric Acids↗

The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat.

The nasal absorption of a range of water-soluble compounds with different molecular weights, 4-oxo-4H-1-benzopyran-2-carboxylic acid (mol. wt 190), p-aminohippuric acid (mol. wt 194), inulin (mol. wt 5200) and dextran (mol. wt 70,000), has been investigated in the male Wistar rat. Compounds were instilled into the nasal cavities of anaesthetized animals, and for comparison, similar doses were administered intravenously. Serial samples of bile and urine were collected for up to 6 h. Nasal absorption, estimated by comparison of the extent of excretion in bile and urine following intranasal and intravenous administration, was 100% for 4-oxo-4H-1-benzopyran-2-carboxylic acid (1 mg kg-1), 75% for p-aminohippuric acid (1 mg kg-1), 15% for inulin (0.1 mg kg-1) and 2.8% for dextran (0.25 mg kg-1). The log molecular weight gave a good linear correlation with the log per cent intranasally absorbed (correlation coefficient of -0.996). From the molecular weight relationship, these data infer aqueous channel mechanisms for the nasal absorption of water-soluble compounds.

Absorption↗

The natriuretic effect of the organic acid para-aminohippurate.

Infusion of para-aminohippurate (PAH) during renal clearance experiments has been shown to increase urinary sodium excretion (UNAV). In addition, it has recently been suggested that accumulation of PAH and/or related compounds may be responsible for the increased UNAV per nephron in chronic renal failure. Therefore, studies were designed to determine the mechanism for the natriuretic effect of PAH. PAH administration at (0.19 mM per minute) into the dog renal artery led to an average increase in UNAV of 56+/-11 muEq per minute. Mannitol given at this rate (0.19 mM per minute) led to an increase in UNAV of 26+/-10 muEq per minute, which was less than the increase in UNAV with PAH. NA2SO4 given at this (0.19 mEq per minute) or a higher rate (0.60 mEq. per minute) was associated with an increase in UNAV of 53+/-18 and 228+/-38 muEq per minute, respectively. In the PAH and SO4 studies the increase in UPAHV or USO4V was not different from the increase in UNAV. These results suggest that the natriuretic effect of PAH is mainly due to its effect as a nonreabsorbable anion and offer no support for an osmotic effect or a direct effect on active sodium transport.

Aminohippuric Acids↗

Tubular segment-specific biomarkers of nephrotoxicity in the rat.

Segment-specific localization of p-aminohippuric acid accumulation and glutamine synthetase activity along the proximal tubule was investigated in kidneys of rats treated with segment-specific nephrotoxicants such as potassium dichromate (pars convoluta) and hexachloro-1:3-butadiene (pars recta). Potassium dichromate and the highest dose (200 mg/kg b.w.) of hexachloro-1:3-butadiene caused a significant, dose-dependent decrease of p-aminohippuric acid uptake in the renal cortical slices 24 and 48 h after the treatment. In contrast, hexachloro-1:3-butadiene and only the highest dose (40 mg/kg b.w.) of potassium dichromate, caused a significant dose-dependent decrease of glutamine synthetase activity in the kidney beginning 24 h after treatment. Finally, potassium dichromate and the highest dose (200 mg/kg b.w.) of hexachloro-1:3-butadiene (48 h after the treatment) caused a significant dose-dependent loss of kidney protein content. The results suggest that p-aminohippuric acid accumulation is localized in the pars convoluta and confirm that glutamine synthetase is in the pars recta of the rat proximal tubule. p-Aminohippuric acid uptake impairment and glutamine synthetase activity loss caused by the highest doses of hexachloro-1:3-butadiene and potassium dichromate, respectively, suggests that high doses of segment-specific chemicals may involve other portions of the proximal tubule; in addition, the decrease of glutamine synthetase activity caused by potassium dichromate may be related to the protein content loss.

Animals↗

Permeability of the blood-ocular barrier to mannitol and PAH during experimental diabetes.

The simultaneous uptake of mannitol, a passive permeability marker, and the organic acid, p-aminohippuric acid, was measured in the anterior and posterior vitreous and retina. Uptake was determined in control, probenecid treated and streptozocin diabetic rats. The unidirectional influx, calculated as a 10 minute PS product for these compounds, was not increased by 2, 4, or 12 weeks of diabetes. A clearance value, calculated using an experimental time of 60 minutes was also examined in order to gauge efflux of these compounds from the eye. The 60 minute clearance value for mannitol in the retina increased approximately 75% in 2, 4, and 12 week diabetic rats. This was an unexpected result due to the lack of increase in the unidirectional flux of mannitol during these same periods of diabetes, and may represent a change in the passive efflux out of the retina. The 60 minute clearance value for mannitol was not significantly changed in either the anterior or posterior vitreous. Experimental diabetes increased the 60 minute clearance value for PAH for the retina by 40% to 70%. In contrast, diabetes did not increase influx of PAH into the anterior or posterior vitreous. Because the unidirectional influx of PAH into the retina was not increased during diabetes, a decrease in the active transport for organic acids out of the eye is a likely explanation for the increase in the 60 minute clearance value for PAH during diabetes.

Analysis of Variance↗