Benzyl [(11)C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice.

Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several (11)C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding (11)C-labeled organic acids in target tissues. Among the compounds screened, benzyl [(11)C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3(-/-) and Mrp4(-/-) mice, respectively, compared with that of control mice after the intravenous administration of benzyl [(11)C]hippurate. Benzyl [(11)C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively.

Systemic exposure to benzoic acid and hippuric acid following topical application of clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel in Japanese patients with acne vulgaris.

Clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel (CLDM/BPO3%) is a topical product for the treatment of acne vulgaris. In this study, plasma and urine concentrations of benzoic acid (BA) and hippuric acid (HA) were analyzed to estimate the pharmacokinetics (PK) of BPO after application of CLDM/BPO3% twice-daily for 7 days in Japanese patients with acne vulgaris. Seven-day repeated application of CLDM/BPO3% appears to be safe in this patient population. Concentrations of plasma and urine BA were below the limit of quantification before and after repeated application in most of the 12 adult male patients. Mean difference in Cmax and AUC0-last for plasma HA indicated increased exposures after repeated application, but with wide 90% confidence intervals. Mean Ae0-12 for urine HA was similar before and after repeated application. Repeated application of CLDM/BPO3% is thus unlikely to result in accumulation of BA and HA. The study suggests negligible systemic exposure to BPO metabolites from CLDM/BPO3% after 7-day repeated application in male patients with acne vulgaris.

Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era.

In the era of multidrug resistance, it is critical to utilize antibiotics in an appropriate manner and to identify new treatments or revisit the use of 'forgotten' drugs. Because urinary tract infections (UTIs) are common, particularly in an increasing elderly population, the 'forgotten' drug, methenamine, may become important as a preventive therapy for recurrent UTIs. Methenamine, a urinary antibacterial agent, can be used as methenamine hippurate or methenamine mandelate preparations and is United States Food and Drug Administration-approved. This article discusses the place of preventive therapy for recurrent UTIs, chemistry, mechanism of action, pharmacology, clinical uses, dosage, adverse reactions and safety, and drug interactions of methenamine. Because of its unique antiseptic property, the authors suggest that methenamine should be considered when more commonly used antibiotics fail to suppress recurrent UTIs.

Pharmacokinetic study of multiple active constituents after oral gavage of Guizhi decoction in rats using a LC-MS/MS method.

Guizhi decoction (GZD) is a classic traditional Chinese medicine formula, clinically used for the treatment of influenza, common cold, and other pyretic conditions. A sensitive, specific, and validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to investigate the pharmacokinetic properties of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid in rat. After single dose oral administration of 7.9 g extract/kg body weight GZD in rats, plasma concentrations of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid were measured by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data. The values of AUC0-t, half-life (t 1/2), and C max were 7.2 ± 2.3 µg h/mL, 1.2 ± 0.3 h, and 9.2 ± 5.2 µg/mL for cinnamic acid, 53 ± 31 µg h/mL, 2.8 ± 2.0 h, and 17 ± 3 µg/mL for hippuric acid, 1.1 ± 0.5 µg h/mL, 1.9 ± 1.1 h, and 0.6 ± 0.3 µg/mL for paeoniflorin, and 11 ± 6 µg h/mL, 6.6 ± 2.5 h, and 0.9 ± 0.6 µg/mL for glycyrrhetic acid, respectively. The results would offer useful information for effective components of GZD in vivo.

Evaluation of metabolism and disposition of GDC-0152 in rats using 14C labeling strategy at two different positions: a novel formation of hippuric acid from 4-phenyl-5-amino-1,2,3-thiadiazole.

The compound (S)-1-[(S)-2-cyclohexyl-2-([S]-2-[methylamino]propanamido)acetyl]-N-(4-phenyl-1,2,3-thiadiazol-5-yl)pyrrolidine-2-carboxamide (GDC-0152) is a peptidomimetic small molecule antagonist of inhibitor of apoptosis (IAP) proteins with antitumor activity. The mass balance, pharmacokinetics, tissue distribution and metabolism of GDC-0152 was investigated in rats following intravenous administration of 15 mg/kg of [(14)C]GDC-0152, labeled either at the terminal phenyl ring (A) or at the carbonyl of the 2-amino-2-cyclohexylacetyl moiety (B). In rats, 92.2%-95.1% of the radiolabeled GDC-0152 dose was recovered. Approximately 62.3% and 25.1% of A was excreted in urine and feces, respectively. By contrast, B was excreted almost equally in urine (27.2%), feces (32.2%), and expired air (27.5%). GDC-0152 underwent extensive metabolism, with less than 9% of the dose recovered as parent in excreta. Similarly, in plasma, GDC-0152 represented 16.7% and 7.5% of the area under the curve of the total radioactivity for A and B, respectively. The terminal half-life (t(1/2)) for total radioactivity was longer for B (21.2 hours) than for A (4.59 hours). GDC-0152 was highly metabolized via oxidation and amide hydrolysis, followed by subsequent sulfation and glucuronidation. The most abundant circulating metabolites were the amide hydrolyzed products, M26, M28, M30, M31, and M34, which ranged from 3.5% to 9.0% of total radioactivity. In quantitative whole-body autoradiography studies, the residence of radioactivity in tissues was longer for B than for A, which is consistent with the t(1/2) of the total radioactivity in circulation. A novel 4-phenyl-5-amino-1,2,3-thiadiazole (M28) oxidative cleavage resulted in the formation of hippuric acid (M24). This biotransformation was also observed in rat hepatocyte incubations with para-substituted M28 analogs. In addition, the formation of M24 was inhibited by 1-aminobenzotriazole, which points to the involvement of P450 enzymes.

Single-step radiosynthesis and in vivo evaluation of a novel fluorine-18 labeled hippurate for use as a PET renal agent.

OBJECTIVE: The objective of this study was to investigate a new fluorine-18 labeled hippurate, m-cyano-p-[(18)F]fluorohippurate ([(18)F]CNPFH), as a potential radiopharmaceutical for evaluating renal function by PET. METHODS: [(18)F]CNPFH was synthesized by a direct one-step nucleophilic aromatic substitution using an (18)F-for-[N(CH(3))(3)](+)-reaction. In vivo stability was determined by HPLC analysis of urine collected from a healthy rat at 30min p.i. of [(18)F]CNPFH. The plasma protein binding (PPB) and erythrocyte uptake of [(18)F]CNPFH were determined using blood collected from healthy rats at 5min p.i. Biodistribution studies were conducted in healthy rats at 10min and 1h p.i. of [(18)F]CNPFH. Dynamic PET/CT imaging data were acquired in normal rats. For comparison, the same rats underwent an identical imaging study using the previously reported p-[(18)F]fluorohippurate ([(18)F]PFH) renal agent. RESULTS: [(18)F]CNPFH demonstrated high in vivo stability with no metabolic degradation. The in vivo PPB and erythrocyte uptake of [(18)F]CNPFH were found to be comparable to those of [(18)F]PFH. Biodistribution and dynamic PET/CT imaging studies revealed a rapid clearance of [(18)F]CNPFH primarily through the renal-urinary pathway. However, unlike [(18)F]PFH, a minor (about 12%) fraction was eliminated via the hepatobiliary route. The PET-derived [(18)F]CNPFH renograms revealed an average time-to-peak (T(max)) of 3.2±0.4min which was similar to [(18)F]PFH, but the average time-to-half-maximal activity (11.4±2.8min) was found to be higher than that of [(18)F]PFH (7.1±1.3min). CONCLUSIONS: Our in vivo results indicate that [(18)F]CNPFH has renogram characteristics similar to those of [(18)F]PFH, however, the unexpected hepatobiliary elimination is adding undesirable background signal in the PET images.

Preparation of hippurate-zinc layered hydroxide nanohybrid and its synergistic effect with tamoxifen on HepG2 cell lines.

BACKGROUND: A new simple preparation method for a hippurate-intercalated zinc-layered hydroxide (ZLH) nanohybrid has been established, which does not need an anion-exchange procedure to intercalate the hippurate anion into ZLH interlayers. METHODS: The hippuric acid nanohybrid (HAN) was prepared by direct reaction of an aqueous suspension of zinc oxide with a solution of hippuric acid via a one-step method. RESULTS: The basal spacing of the nanohybrid was 21.3 Å, indicating that the hippurate anion was successfully intercalated into the interlayer space of ZLH, and arranged in a monolayer fashion with the carboxylate group pointing toward the ZLH inorganic interlayers. A Fourier transform infrared study confirmed the formation of the nanohybrid, while thermogravimetry and differential thermogravimetry analyses showed that the thermal stability of the nanohybrid was markedly enhanced. The loading of hippurate in the nanohybrid was estimated to be about 38.7% (w/w), and the release of hippurate from the nanohybrid was of a controlled manner, and therefore the resulting material was suitable for use as a controlled-release formulation. HAN has synergistic properties with tamoxifen toward a HepG2 cell line, with an IC50 value of 0.35 compared with hippurate. In the antiproliferative assay, the ratio of viable cells account for cells treated by the combination tamoxifen with HAN to untreated cells was sharply reduced from 66% to 13% after 24 and 72 hours, respectively. CONCLUSION: The release of hippuric acid anions from HAN occurred in a controlled manner, and the resulting material is suitable for a controlled-release formulation.

Oral administration of ethanol with aspirin increases the concentration of salicylic acid in plasma and organs, especially the brain, in mice.

Aspirin (acetylsalicylic acid) has been widely used as an over-the-counter drug to relieve pain throughout the world. In suicide attempts, aspirin is one of the most common drugs taken in large quantities. The concentration of salicylic acid shows a low-level distribution in the mouse brain, a site that may be critical regarding the expression of symptoms (e.g. hyperpnea, coma, convulsion and tremor) during acute aspirin toxicity. Therefore, it was suggested that sensitivity to salicylic acid concerning acute toxicity was higher in the brain than in other organs. Moreover, it is thought that it is common for aspirin and ethanol to be ingested at the same time. Therefore, the present study was designed to investigate the influence of ethanol on the distribution of salicylic acid, which is a primary metabolite of aspirin, and its related metabolite, salicyluric acid. The oral co-administration of aspirin (0.5g/kg) and ethanol (2.5g/kg; 10ml/kg of 25% (w/v)) enhanced the concentrations of salicylic acid in the plasma and organs, especially in the brain, compared with the aspirin alone-treated group. On the other hand, ethanol did not influence the concentrations of salicyluric acid in the plasma and kidney compared with the aspirin alone-treated group. These results suggest that ethanol enhances aspirin absorption from the gastrointestinal tract but has no influence on its metabolism. Thus, it is dangerous to ingest the alcohol and aspirin at the same time, as this may exacerbate the acute toxicity of aspirin.

Antioxidant metabolism induced by quinic acid. Increased urinary excretion of tryptophan and nicotinamide.

For over 50 years, hippuric/quinic acids were believed to have no biological efficacy. Here data are presented to support the hypothesis that quinic acid is not responsible for any efficacy, but rather that quinic acid nutritionally supports the synthesis of tryptophan and nicotinamide in the gastrointestinal (GI) tract, and that this in turn leads to DNA repair enhancement and NF-kB inhibition via increased nicotinamide and tryptophan production.Moreover, it is shown that quinic acid is a normal constituent of our diet, capable of conversion to tryptophan and nicotinamide via the GI tract microflora, thus providing an in situ physiological source of these essential metabolic ingredients to humans. The concentrations of quinic and hippuric acids in the diet were dependent on each other when analysed in urine, as was evidenced by a significant linear regression analysis that included unsupplemented control subjects (n = 45, p < 0.001). Thus, these ingredients were identified as major dietary components, and not simply originating from environmental pollution as previously had been thought.

Synthesis and properties of N,N'-bis(5-aminosalicyl)-L-cystine as a colon-specific deliverer of 5-aminosalicylic acid and cystine.

N,N(')-bis(5-aminosalicyl)-L-cystine (5-ASA-Cys) was prepared by a simple synthetic route. 5-ASA-Cys was not degraded in pH 1.2 and 6.8 buffer solutions, and in the homogenates of the upper intestine. In marked contrast, 5-ASA-Cys was deconjugated extensively to liberate 5-ASA in the cecal contents. Upon oral administration of 5-ASA-Cys to rats, the plasma concentration of 5-ASA-Cys was extremely low and the urinary recovery of 5-ASA-Cys was approximately 10% of the dose. These results suggest that 5-ASA-Cys administered orally is delivered efficiently to the large intestine followed by deconjugation to liberate 5-ASA and cystine.

Proteinuria-lowering effect of heparin therapy in diabetic nephropathy without affecting the renin-angiotensin-aldosterone system.

Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with (99m)Tc-DTPA and (131)I-hippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin-angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis.

Renal clearance of endogenous hippurate correlates with expression levels of renal organic anion transporters in uremic rats.

Hippurate (HA) is a harmful uremic toxin that accumulates during chronic renal failure, and failure of the excretion system for uremic toxins is thought to be responsible. Recently, we reported that rat organic anion transporter 1 (rOat1) is the primary mediator of HA uptake in the kidney, and so now we have studied the pharmacokinetics and tissue distribution of HA after a single i.v. dose of HA to normal and 5/6 nephrectomized rats (5/6Nx rats). In control rats, the renal and biliary clearances of HA were 18.1 and 0.1 ml/min/kg, respectively. Plasma clearance decreased as dosage increased from 0.1 to 5 mg/kg, which suggests that renal tubular secretion is the primary route for elimination of HA. The plasma clearance of HA was significantly decreased in 5/6 Nx rats compared with normal rats. In 5/6 Nx rats, renal clearance of endogenous HA correlated more closely with clearance of p-aminohippurate than with that of creatinine. Protein expression of rOat1 and rOat3, assessed by Western blot analysis, was decreased in 5/6 Nx rats. Furthermore, in 5/6 Nx rats, the renal secretory clearance of endogenous HA correlated closely with protein expression of renal rOats. Thus, HA is primarily eliminated from the plasma via the kidney by active tubular secretion. The renal clearance of endogenous HA seems to be a useful indicator of changes in renal secretion that accompany the reduced levels of OAT protein in chronic renal failure.

Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats.

PURPOSE: Evidence suggests that uremic toxins such as hippurate (HA), indoleacetate (IA), indoxyl sulfate (IS), and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) promote the progression of renal failure by damaging tubular cells via rat organic anion transporter 1 (rOat1) and rOat3 on the basolateral membrane of the proximal tubules. The purpose of the current study is to evaluate the in vivo transport mechanism responsible for their renal uptake. METHODS: We investigated the uremic toxins transport mechanism using the abdominal aorta injection technique [i.e., kidney uptake index (KUI) method], assuming minimal mixing of the bolus with serum protein from circulating serum. RESULTS: Maximum mixing was estimated to be 5.8% of rat serum by measuring estrone sulfate extraction after addition of 0-90% rat serum to the arterial injection solution. Saturable renal uptake of p-aminohippurate (PAH, K(m) = 408 microM) and benzylpenicillin (PCG, K(m) = 346 microM) was observed, respectively. The uptake of PAH and PCG was inhibited in a dose-dependent manner by unlabeled PCG (IC(50) = 47.3 mM) and PAH (IC(50) = 512 microM), respectively, suggesting that different transporters are responsible for their uptake. A number of uremic toxins inhibited the renal uptake of PAH and PCG. Excess PAH, which could inhibit rOat1 and rOat3, completely inhibited the saturable uptake of IA, IS, and CMPF by the kidney, and by 85% for HA uptake. PCG inhibited the total saturable uptake of HA, IA, IS, and CMPF by 10%, 10%, 45%, and 65%, respectively, at the concentration selective for rOat3. CONCLUSIONS: rOat1 could be the primary mediator of the renal uptake of HA and IA, accounting for approximately 75% and 90% of their transport, respectively. rOat1 and rOat3 contributed equally to the renal uptake of IS. rOat3 could account for about 65% of the uptake of CMPF under in vivo physiologic conditions. These results suggest that rOat1 and rOat3 play an important role in the renal uptake of uremic toxins and the induction of their nephrotoxicity.

Nuclear magnetic resonance spectroscopic based studies of the metabolism of black tea polyphenols in humans.

Epidemiological studies indicate that a high intake of flavonoids is associated with an improved health status. Tea is one of the most abundant sources of flavonoids in the human diet. The bioavailability and biotransformation of tea flavonoids are, however, not clearly understood. The aim of the present study was to investigate the metabolism of black tea via a nonspecific screening method. (1)H nuclear magnetic resonance (NMR) spectroscopy was used to obtain nonselective profiles of urine samples collected from three human volunteers before and after a single dose of black tea. The complex spectroscopic profiles were interpreted with the use of pattern recognition techniques. Hippuric acid was confirmed as the major urinary black tea metabolite. One previously unknown metabolite was detected and identified as 1,3-dihydroxyphenyl-2-O-sulfate (sulfate conjugate of pyrogallol) using HPLC directly coupled to mass spectrometry and (1)H NMR spectroscopy. This study shows that NMR-pattern recognition studies can be used for the discovery of unknown flavonoid metabolites in humans.

Dynamic renal blood flow measurement by positron emission tomography in patients with CRF.

BACKGROUND: Positron emission tomography (PET) is a functional imaging device that allows dynamic regional blood flow measurements. We performed a study to test whether PET could detect acute changes in renal blood flow (RBF) in patients with chronic renal failure (CRF). METHODS: RBF was measured by means of PET (PET-RBF) using oxygen 15-labeled water (H2(15)O) in eight men with hypertension and moderate CRF before and 5, 40, 80, and 120 minutes after the injection of quinaprilat (10 mg intravenously). Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured simultaneously by para-aminohippuric acid (PAH-ERPF) and inulin clearances before and 20, 60, 100, and 140 minutes after quinaprilat injection. RESULTS: Baseline RBF and ERPF were decreased in all patients (221 +/- 20 mL/min/100 g and 225 +/- 38 mL/min/1.73 m2, respectively). PET-RBF increased significantly after quinaprilat injection (+15%, +26%, +19%, and +23% versus baseline; P < 0.003). PAH-ERPF did not increase significantly (-6%, +12%, +20%, and +15% versus baseline; P = 0.15). GFR (50.1 +/- 8.9 mL/min/1.73 m2 at baseline) did not change significantly after quinaprilat injection; however, filtration fraction (GFR-ERPF ratio) decreased significantly from 0.23% +/- 0.02% to 0.20% +/- 0.02% (P = 0.0004). Mean arterial pressure decreased significantly after quinaprilat injection (P < 0.005). CONCLUSION: This study dynamically measured RBF by means of PET in patients with CRF for the first time. It showed that RBF rapidly increased after quinaprilat injection. PET using H2(15)O is a powerful method for the noninvasive measurement of dynamic changes in RBF that remain undetected by PAH clearance.

Polyphenols from alcoholic apple cider are absorbed, metabolized and excreted by humans.

We determined the uptake and excretion of low doses of polyphenols in six subjects who each consumed 1.1 L of an alcoholic cider beverage. Over a 24-h period, no phloretin was detected in plasma (detection limit = 0.036 micromol/L), but 21 +/- 5% of the dose (4.8 mg) was excreted in the urine. In contrast, from a low dose of 1.6-mg quercetin equivalents, no quercetin was found in urine or plasma, but 3'-methyl quercetin was detected in plasma [C(max) (maximum concentration) = 0.14 +/- 0.19 micromol/L; range: 0 to 0.44 micromol/L]. No flavanol monomers (dose of free (+)-catechin and (-)-epicatechin = 3.5 mg) were detected in urine or plasma (detection limit: 0.01 micromol/L). Caffeic acid (total dose including esters = 11 mg) was detected only in plasma within 2 h, with C(max) = 0.43 +/- 0.3 micromol/L (range: 0.18 to 0.84 micromol/L). An almost 3-fold increase in hippuric acid was detected in 24-h urine (74 +/- 29 micromol/L; range: 38-116 micromol/L), compared with a prestudy value of 19 +/- 9 micromol/L. These data show that polyphenols are taken up from cider, that phloretin is excreted in the urine and suggest that low doses of quercetin are extensively methylated in humans.

Development of a physiologically based pharmacokinetic model of organic solvent in rats.

A physiologically based pharmacokinetic model of the transfer of organic solvents in rat bodies was developed. The model has six compartments, i.e. lungs, vessel-rich tissue, muscles, fat tissue, tail, and liver, each being interconnected by the blood flow system. The transfer of organic solvents was expressed by simultaneous differential equations, which were then solved numerically by a personal computer using a simple spreadsheet program. m -xylene was used to represent organic solvents. The physiological parameters for rats (alveolar ventilation, cardiac output, tissue volume, tissue blood flow, etc.) and physicochemical or biochemical properties (blood/air partition coefficient, tissue/blood partition coefficients, metabolic constants, etc.) of m -xylene were based on the data obtained from the literature and our experiments. The partition coefficient of m -xylene for the tail and the blood flow and the volume of the rat tail were experimentally determined with adult rats. The results of simulation of rat exposure to m -xylene (50 and 500 ppm for 6 h) were essentially in good agreement with the experimental data on rats, i.e. the parent compound (m -xylene) concentration in the tail blood and the cumulative excretion of the metabolites in the urine were consistent.

Synthesis and in vitro/in vivo evaluation of 5-aminosalicyl-glycine as a colon-specific prodrug of 5-aminosalicylic acid.

A simple synthetic route for the preparation of amino acid conjugate of 5-aminosalicylic acid (5-ASA) was exploited and prepared 5-aminosalicyl-glycine (5-ASA-Gly) in good yield. In vitro and in vivo properties of 5-ASA-Gly as a colon-specific prodrug of 5-ASA were investigated using rats as the test animal. Incubation of 5-ASA-Gly with cecal or colonic contents at 37 degrees C released 5-ASA in 65 or 27% of the dose in 8 h, respectively. No 5-ASA was detected from the incubation of 5-ASA-Gly with the homogenates of stomach or small intestine. Plasma concentration of 5-ASA-Gly decreased rapidly after intravenous administration of 5-ASA-Gly, and no 5-ASA was detected in the blood, which indicated 5-ASA-Gly was not degraded in the plasma. After oral administration of 5-ASA-Gly, about 50% of the administered dose was recovered as 5-ASA and N-acetyl-ASA and 3% as 5-ASA-Gly from feces and 14% as 5-ASA-Gly and 28% as 5-ASA and N-acetyl-ASA from urine in 24 h. These results suggested that a large fraction of 5-ASA-Gly was delivered to the large intestine and activated to liberate 5-ASA. For comparison, total recovery of 5-ASA and N-acetyl-5-ASA from feces after oral administration of 5-ASA-Gly was greater than that from sulfasalazine, which is one of the most commonly prescribed prodrugs of 5-ASA.

Effect of chlorophenoxyacetic acid herbicides on glycine conjugation of benzoic acid.

1. 2,4-Dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) (0.1-0.5 mmol/kg i.p.) delayed the disappearance of injected benzoate from blood and diminished the urinary excretion of the formed benzoylglycine, but elevated the blood levels of benzoylglycine in rat, suggesting that these herbicides interfere with both the formation and the renal transport of benzoylglycine. 2. Inhibition of the renal excretion of benzoylglycine by 2,4-D or 2,4,5-T (0.5 mmol/kg i.p.) was directly demonstrated in rat injected with benzoylglycine. 3. Inhibition of benzoylglycine formation from benzoic acid by 2,4-D or 2,4,5-T (0.5 mmol/kg i.p.) was directly demonstrated in renal pedicles-ligated rats injected with benzoate. 4. Neither 2,4-D nor 2,4,5-T influenced the hepatic concentrations of ATP, coenzyme A (CoA) or glycine; therefore, it is unlikely that they inhibit glycine conjugation of benzoic acid by diminishing the availability of co-substrates. 5. Although the chlorophenoxyacetic acids did not appear to be a substrate for the mitochondrial acyl-CoA synthetases, both 2,4-D and 2,4,5-T diminished the activity of benzoyl-CoA synthetase (but not that of benzoyl-CoA:glycine N-acyltransferase) in solubilized hepatic mitochondria. These findings suggest that 2,4-D and 2,4,5-T impair benzoylglycine formation in rat by inhibiting benzoyl-CoA synthetase.

Influence of nutritional status on the pharmacokinetics of acetylsalicylic acid and its metabolites in children with autoimmune disease.

BACKGROUND: It is unknown whether nutritional status associated with autoimmune disease alters the pharmacokinetics of acetylsalicylic acid (ASA) and its metabolites. OBJECTIVE: We studied the effects of the nutritional status of children with autoimmune disease on the disposition of ASA and its metabolites. DESIGN: A prospective, open-label study was performed with 21 children aged 3-15 y who required ASA therapy. Children received 25 mg ASA/kg orally. Blood samples were drawn before and 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, and 24.0 h after ASA administration; urine samples were collected at different intervals. ASA and its metabolites were measured in plasma and urine. Nutritional status was assessed previously. RESULTS: The ASA maximum plasma concentration, area under the curve, and total clearance were significantly lower in underweight children than in normal-weight children. The elimination rate constants of gentisic acid (GA), salicyluric acid (SUA), and salicylic acid (SA) in plasma were slower for underweight children than for normal-weight children. The distribution volume of SUA increased significantly (r = 0.92) when the deficit percentage in weight-for-height increased. Underweight children excreted less GA and SA, but more SUA, than did normal-weight children. CONCLUSIONS: These observations suggest a decrease in the hydrolysis and oxidative reactions of the metabolic pathway of ASA and its metabolites in underweight children. The study illustrates the need for pharmacokinetic data to establish the individual doses of drugs, particularly in conditions that alter nutritional status.