Influence of Malnutrition on the Disposition of Metronidazole in Rats

The influence of dietary protein deficiency on the disposition of metronidazole and its two major metabolites was examined in male Sprague–Dawley rats fed for 4 weeks on a 23% (control-) or a 5% (low-) protein diet ad libitum. Following an intravenous bolus dose of 10 mg/kg metronidazole hydrochloride, blood samples were obtained serially for a period of 24 hr after drug administration. Serum concentration–time data were analyzed by nonlinear least-squares regression, as well as noncompartmental techniques. The average mean residence time (MRT) was significantly prolonged by 48%, while the systemic clearance (Cl) was decreased by 42% in the protein-deficient rats. Since there was no alteration in the apparent steady-state volume of distribution (V _ss), the mean harmonic half-life was increased from 2.9 to 5.0 hr in the protein-deficient rats. Although the percentage of metronidazole recovered as total drug in the urine over 24 hr was not significantly different between the two groups of animals, rats on a low-protein diet excreted a significantly smaller percentage of the administered dose as unchanged metronidazole (mean ± SD, 24.6 ± 3.8 vs 36.5 ± 12%) and a larger percentage (16.7 ± 2.6 vs 8.3 ± 1.8%) as the hydroxylated metabolite. No significant difference in the partial metabolic clearance of the hydroxylated metabolite of metronidazole was seen between the two groups of animals; however, there was a significant decrease in the renal clearance of metronidazole (1.45 ± 0.68 vs 0.55 ± 0.06 ml/min/kg) in the rats fed a low-protein diet. We conclude that the decreased clearance of metronidazole in protein deficiency is a result primarily of the decreased glomerular filtration rate, decreased biliary excretion, and/or increased net tubular reabsorption of metronidazole.     

Effect of Age on the Disposition and Tissue Clearances of Fluorinated Pyrimidines in Rats

The age dependency of the elimination and tissue clearances of 5-fluorouracil (FU) and its nucleoside analog, 5-deoxy-5-fluorouridine (dFUR), was investigated in 2 to 12 months old female Fischer rats. In all age groups, the blood clearances of dFUR at infusion rates of 500 and 750 mg kg^–1 day^–1 and of FU at 25 and 35 mg kg^–1 day^–1 were independent of the dose; however, the clearance of FU at a higher infusion rate of 50 mg kg^–1 day^–1 was significantly lower than at 25 mg kg^–1 day^–1. An inverse relationship between animal age and clearance was observed for dFUR at both 500 and 750 mg kg^–1 day^–1 doses, and for FU at the 50 mg kg^–1 day^–1 dose. By contrast, the FU clearance at the 25 and 35 mg kg^–1 day^–1 doses was independent of age. To examine the age effect on the metabolic activities of major eliminating organs, the metabolism of dFUR by liver and small intestine in young and old rats was compared using 13,000 × g supernatant fractions of the tissue homogenates. Data were computer-fitted to the Michaelis-Menten equation. The Km for both tissues of both age groups was approximately 120 µg ml^–1. The intrinsic clearance (Vmax/Km) of dFUR was 5 ml kg^–1 min^–1 in the liver and 8 ml kg^–1 min^–1 in the intestine. The intestinal intrinsic clearance was independent of animal age, but the hepatic intrinsic clearance was significantly decreased in the older rats. The blood concentrations of FU derived as a metabolite from dFUR were also dependent on the animal age; an elevated FU concentration was associated with a lower dFUR metabolic clearance in the old rats. These data indicate that the elimination of FU and dFUR in rats is age-dependent, and that the systemic concentration of FU, a determinant of dFUR selectivity, is elevated in older animals.     

Effects of Disopyramide and Verapamil on Renal Disposition and Nephrotoxicity of Cisplatin in Rats

Purpose. The purpose of this study was to determine the effects of disopyramide and verapamil on the renal handling of cisplatin (CDDP) and nephrotoxicity in rats. The stereoselective effect of verapamil was also studied. Methods. CDDP was administered to rats by i.v. bolus injection or by infusion at a constant rate with or without concomitant administration of racemic disopyramide, racemic verapamil, or each verapamil enantiomer. The concentrations of CDDP in plasma and in the kidney and liver were determined by HPLC. In separate experiments, CDDP was administered as described above, and blood urea nitrogen (BUN) was monitored for 7 days. Results. The BUN level after administration of CDDP was significantly reduced by coadministration of either disopyramide or verapamil. Renal accumulation of CDDP was significantly reduced by these drugs, whereas accumulation into the liver was not significantly changed. The relationship between the BUN levels and the area under the curve of CDDP concentration in the kidney versus time (AUC_k) was analyzed using a sigmoid E_max model; this showed that the reduced BUN levels were explained by the AUC_k. Furthermore, verapamil showed stereoselective inhibition of the renal accumulation of CDDP. Conclusions. The renal accumulation of CDDP was inhibited by disopyramide and verapamil, and this inhibition resulted in the amelioration of nephrotoxicity.     

Alterations in Renal Uptake Kinetics of the Xanthine Derivative Enprofylline in Endotoxaemic Mice

The pharmacokinetics and renal uptake of enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg^?1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of enprofylline after constant infusion for 1 h. The renal uptake rate of enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (V_max) from 17.3 to 32.2 μg h^?1 g^?1 of kidney and in the Michaelis–-Menten constant (K_m) from 2.7 to 21.7 μg mL^?1 and decrease in the nonsaturable uptake rate constant (K_d) from 0.87 to 0.43 mL h^?1 g^?1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of enprofylline by inducing a decrease in the renal uptake ability.     

The Effects of N-Benzoyl-β-alanine,a New Nephroprotective Drug,on the Distribution and Renal Excretion of Enprofylline in Rats

Abstract— The effects of the new nephroprotective drug N-benzoyl-β-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2·5 mg kg^?1 under three different steady-state plasma BA concentrations (100,200 and 400 μg mL^?1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 μg mL^?1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 μg mL^?1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.     

Relationships between the Renal Handling of DMPS and DMSA and the Renal Handling of Mercury

Within the body of this review, we provide updates on the mechanisms involved in the renal handling mercury (Hg) and the vicinal dithiol complexing/chelating agents, 2,3-bis(sulfanyl)propane-1-sulfonate (known formerly as 2,3-dimercaptopropane-1-sulfonate, DMPS) and meso-2,3-bis(sulfanyl)succinate (known formerly as meso-2,3-dimercaptosuccinate, DMSA), with a focus on the therapeutic effects of these dithiols following exposure to different chemical forms of Hg. We begin by reviewing briefly some of the chemical properties of Hg, with an emphasis on the high bonding affinity between mercuric ions and reduced sulfur atoms, principally those contained in protein and nonprotein thiols. A discussion is provided on the current body of knowledge pertaining to the handling of various mercuric species within the kidneys, focusing on the primary cellular targets that take up and are affected adversely by these species of Hg, namely, proximal tubular epithelial cells. Subsequently, we provide a brief update on the current knowledge on the handling of DMPS and DMSA in the kidneys. In particular, parallels are drawn between the mechanisms participating in the uptake of various thiol S-conjugates of Hg in proximal tubular cells and mechanisms by which DMPS and DMSA gain entry into these target epithelial cells. Finally, we discuss factors that permit DMPS and DMSA to bind intracellular mercuric ions and mechanisms transporting DMPS and DMSA S-conjugates of Hg out of proximal tubular epithelial cells into the luminal compartment of the nephron, and promoting urinary excretion.     

梗阻性黄疸对大鼠肾小管上皮细胞的影响

目的研究不同时相梗阻性黄疸(Obstructive jaundice,OJ)大鼠肾小管上皮细胞病理学改变的规律及其机制。方法实验大鼠分为正常对照组(Norm control,N组),假手术组(Shamoperation,SO组),胆总管结扎组(Common bile duct ligation,CBDL组)。其中CBDL组又分为CB-DL3d、CBDL7d、CBDL11d三亚组。模型建立后,使用鲎试剂动态浊度、生化和末端脱氧核甘酸介导生物素标记(TUNEL)技术测量不同组别,不同时相OJ大鼠内毒素(ET)、一氧化氮(NO)、胆红素(TB)、胆汁酸(TBA)、肌肝(Cr)、尿素氮(BUN)水平及肾小管上皮细胞凋亡指数(AI),并进行多元相关性分析。结果胆管梗阻3天时肾脏形态学未见明显改变;7天时可观察到一定数量的肾小管上皮细胞凋亡,充血水肿;11天时凋亡细胞明显增多,同时肾小管上皮细胞严重充血、肿胀,但无坏死特征性表现。多元分析发现,ET与肾小管上皮细胞凋亡水平关系密切(P<0.05)。结论细胞凋亡是OJ引起肾小管上皮细胞损伤的主要方式,ET与之密切相关。     

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

PURPOSE: The lithium disposition to cerebrospinal fluid (CSF) was evaluated in rats with acute renal failure (ARF) to examine whether electrolyte homeostasis of the CSF is perturbed by kidney dysfunction. In addition, the effects of renal failure on choroid plexial expressions of the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) and Na(+)/H(+) exchanger (NHE1) were also studied. METHODS: After lithium was intravenously administered at a dose of 4 mmol/kg, its concentration profile in plasma was evaluated by collecting plasma specimens, while that in CSF was monitored with a microdialysis probe in the lateral ventricles. NKCC1 and NHE1 expressions were measured via the Western immunoblot method using membrane specimens prepared from the choroid plexus in normal and ARF rats. RESULTS: The lithium concentration in CSF of ARF rats was 30% lower than that of normal rats, while their plasma lithium profiles were almost the same, indicating that the lithium disposition to CSF was decreased in ARF rats. It was revealed that the choroid plexial expression of NKCC1 was increased by 40% in ARF rats, but that of NHE1 was unchanged. CONCLUSION: ARF decreases the lithium disposition to CSF, possibly by promoting lithium efflux from CSF due to increased NKCC1 expression in the choroid plexus.     

促红细胞生成素对慢性肾功能衰竭大鼠肾功能的影响

目的:研究促红细胞生成素(EPO)对慢性肾功能衰竭(CRF)大鼠肾功能的影响及其作用机制.方法:将5/6肾切除大鼠随机分为3组:Ⅰ组为假手术组;Ⅱ组为CRF组;Ⅲ组为给予促红细胞生成素的CRF组.第2次术后8周检测各组血压、尿蛋白、血清尿素氮、血肌酐、血红蛋白;观察肾组织病理改变,检测血清及肾组织中血红蛋白氧合酶 1(HO 1)活性;用免疫组化方法检测HO 1在肾脏中的表达.结果:Ⅲ组与Ⅱ组比较,血压、尿蛋白、血肌酐及尿素氮水平明显降低(P＜0.05),肾小球系膜增生及间质纤维化程度明显减轻(P＜0.05);HO 1活性检测显示,Ⅲ组大鼠血清中HO 1活性明显高于Ⅱ组(P＜0.05),免疫组化显示Ⅲ组大鼠肾组织中HO 1表达明显高于Ⅱ组(面密度、平均光度)(P＜0.05).结论:EPO使CRF大鼠肾功能得到改善,并使CRF大鼠血清及肾组织中HO 1表达及活性明显升高.     

Influence of Moderate Haemodilution with Fluosol or Normal Saline on Carbaryl Disposition in Sprague-Dawley Rats

In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg^?1 haemodilution with Fluosol or normal saline (0.9% NaCl). Volumes of distribution were significantly reduced after saline haemodilution for 72 h but only at 48 h after Fluosol haemodilution. Fluosol and saline haemodilution had little influence on carbaryl total body clearance (CL). These results indicate that both hepatic and non-hepatic clearance pathways were not influenced by the haemodiluents or the haemodilution procedure.     

The Effect of Lipopolysaccharide on the Disposition of Xanthines in Rats

Abstract— The effect of lipopolysaccharide (LPS) isolated from Klebsiella pneumoniae O3 on the pharmacokinetic behaviour and metabolism of the xanthines, theophylline and 1-methyl-3-propylxanthine (MPX), which are mainly metabolized by the liver, was investigated in rats. LPS was infused at 0·25 mg kg^?1 over a period of 20–30 min, 2 h before the administration of theophylline (10 mg kg^?1) or MPX (2·5 mg kg^?1). Concentrations of both xanthines in plasma and concentrations of the parent drug and metabolites in urine were measured by HPLC. Model-independent methods were applied to estimate the pharmacokinetic parameters for both xanthines. No significant changes in the pharmacokinetic parameters or metabolism of theophylline were observed in rats pretreated with LPS. However, the total body clearance and volume of distribution of MPX were significantly increased by pretreatments with LPS. Significant decreases in the binding capacity and number of binding sites on the albumin molecule were observed in the presence of LPS. Changes occurring in the protein binding behaviour as a result of the introduction of LPS is a primary factor which not only increases the volume of distribution but also increases total body clearance. These results indicate that LPS has no effect on the pharmacokinetics and metabolic pathway of theophylline although it changes the disposition of MPX due to decreases in the extent of the protein binding of MPX which is highly bound to protein.     

Disposition of14C-Erythritol in Germfree and Conventional Rats

The metabolism and disposition of U-¹⁴C-erythritol was examined in four groups of three male and three female, nonfasted rats each. The rats of groups A and D were germfree; the rats of groups B and C were kept under conventional conditions. The rats of group B received an erythritol-supplemented diet for 3 weeks prior to the experiment (adapted rats). The rats of groups A, C, and D were kept on an ordinary diet which was sterile for groups A and D (not adapted rats). On the day of the experiment, each rat was dosed with U-¹⁴C-erythritol by gavage (5 μCi/kg body wt; sp act 50 μCi/g erythritol). The radiochemical purity of the erythritol was 96.43% for groups A–C. Group D, which was attached to the study after evaluation of the results of groups A–C, received a more purified erythritol with a radiochemical purity of 99.46% because the data of group A pointed to a possible interference by a¹⁴C-labeled impurity in the commercial¹⁴C-erythritol. After dosing, respiratory CO₂and urine were collected from each rat at regular intervals for 24 hr. At termination, feces were also collected. The animals were killed and intestinal contents, organs, tissues, and the remaining carcass processed for determination of¹⁴C.¹⁴C was excreted rapidly in the urine of all groups (range of groups A–D: 47.3–60.6% of the administered dose within the first 4 hr). Total 24-hr urinary excretion varied between 67.0% (group B) and 81.4% (group D). HPLC analysis of the urine showed that more than 96% of the eluted radiolabel represented erythritol. Conventional, adapted rats expired more¹⁴CO₂than conventional, unadapted rats [10.9% (B) vs 6.7% (C)]. Germfree rats expired much less¹⁴CO₂[0.8% (A) and 0.3% (D)]. In germfree rats,¹⁴CO₂expiration started shortly after dosing, reaching half of the 24-hr excretion after about 2.5 hr. In conventional rats¹⁴CO₂expiration started with a delay of about 2 hr reaching half the 24-hr excretion after 4–6 hr. The excretion of¹⁴C with feces was similar in all groups (8.3% on average of all rats). Slightly more¹⁴C was retained in the intestinal contents of germfree than conventional rats (1.9 vs 0.5%). The body retention was higher in conventional than in germfree rats (3.4 vs 2.0%). In group D, body retention was lowest (1.6%). The total recovery of¹⁴C was similar in all groups (95.6%, average of all rats). It is concluded that ingested erythritol is efficiently absorbed mainly from the small intestine, is not metabolized to a relevant extent in the body, and is excreted unchanged in the urine. The fraction of erythritol not absorbed is fermented by the gut microflora to intermediate products which are largely absorbed and metabolized. The data support a proposed physiological energy value for erythritol of about 0.5 kcal/g.     

Influence of Cation Transporters (OCTs and MATEs) on the Renal and Hepatobiliary Disposition of [11C]Metoclopramide in Mice

Pharmaceutical Research - To investigate the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of the radiolabeled antiemetic drug [11C]metoclopramide in mice with PET....     

Effects of Probenecid on Hepatic and Renal Disposition of Hexadecanedioate,an Endogenous Substrate of Organic Anion Transporting Polypeptide 1B in Rats

The aim of the present study was to investigate changes in plasma concentrations and tissue distribution of endogenous substrates of organic anion transporting polypeptide (OATP) 1B, hexadecanedioate (HDA), octadecanedioate (ODA), tetradecanedioate (TDA), and coproporphyrin-III, induced by its weak inhibitor, probenecid (PBD), in rats. PBD increased the plasma concentrations of these four compounds regardless of bile duct cannulation, whereas liver-to-plasma (K_p,liver) and kidney-to-plasma concentration ratios of HDA and TDA were reduced. Similar effects of PBD on plasma concentrations and K_p,liver of HDA, ODA, and TDA were observed in kidney-ligated rats, suggesting a minor contribution of renal disposition to the overall distribution of these three compounds. Tissue uptake clearance of deuterium-labeled HDA (d-HDA) in liver was 16-fold higher than that in kidney, and was reduced by 80% by PBD. This was compatible with inhibition by PBD of d-HDA uptake in isolated rat hepatocytes. Such inhibitory effects of PBD were also observed in the human OATP1B1-mediated uptake of d-HDA. Overall, the disposition of HDA is mainly determined by hepatic OATP-mediated uptake, which is inhibited by PBD. HDA might, thus, be a biomarker for OATPs minimally affected by urinary and biliary elimination in rats.     

Metabolic Disposition Study of Chlorinated Hydrocarbons in Rats and Mice

ABSTRACT

Chlorinated hydrocarbons found In a bioassay to be carcinogenic to both B6C3F1 mice and Osborne-Mendel rats (1,2-dichloro-ethane), carcinogenic only to mice (1,1,2-trlchloroethane, 1,1,2,2-tetrachloroethane, hexachloroethane, trlchloroethylene, and tetrachloroethylene), and noncarcinogenlc to either species (1,1-dichloroethane and 1,1,1-trichloroethane) were used to investigate the biochemical bases for tumorigenesis. Studies were conducted after chronic oral dosing of adult mice and rats with the MTD and V4 MTD of each compound. The extent to which the compounds were metabolized in 48 hr, hepatic protein binding, and urinary metabolite patterns were examined. Metabolism of the compounds (mmoles per kg body weight) was 1.7 to 10 times greater In mice than In rats. Hepatic protein binding (nanomole equivalents bound to 1 mg of liver protein) was 1.2 to 8.3 times higher in mice than In rats except for 1,2-dichloroethane and 1,1,1-trichloroethane. The noncarclnogens 1,1-dlchloroethane and 1,1,1-trichloroethane exhibited 2 to 18 times more binding In mice than did the carcinogens 1,2-dichloroethane and 1,1,2-trlchloroeth-ane. Urinary metabolite patterns of the compounds were similar In both species. The biochemical parameters measured provided no clue to differentiate the carcinogens from the noncarclnogens.     

The Disposition of Valproyl Glycinamide and Valproyl Glycine in Rats

Purpose. To investigate the disposition of valproyl glycinamide and valproyl glycine in rats and to compare it with that of valproic acid (VPA) and valpromide which were studied previously. Methods. The study was carried out by monitoring the brain and liver levels of valproyl glycinamide and valproyl glycine (as a function of time after iv dosing) in addition to the regular pharmacokinetic (PK) monitoring of plasma and urine levels of these compounds. Results. The following PK parameters were obtained for valproyl glycinamide and valproyl glycine, respectively: clearance, 7.1 and 16 ml/ min/kg; volume of distribution (Vss), 0.78 and 0.41 1/kg; half-life, 1.1 and 0.37 h; and mean residence time, 1.8 and 0.4 h. The ratios of AUCs of valproyl glycinamide of liver to plasma and brain to plasma were 0.70 and 0.66, respectively. The ratios of the AUCs of valproyl glycine of liver to plasma and brain to plasma were 0.19 and 0.02, respectively. Conclusions. Valproyl glycinamide distributes better in the brain than VPA, a fact which may contribute to its better anticonvulsant activity. Valproyl glycine was barely distributed in the brain, a fact which may explain its lack of anticonvulsant activity. In addition to the liver, the brain was found to be a minor metabolic site of the biotransformation of valproyl glycinamide to valproyl glycine.     

Stereoselective Metabolic Disposition of Enantiomers of Ofloxacin in Rats

1. Stereoselective metabolic disposition of ofloxacin (OFLX) was studied in rats after oral administration of S-(-)-¹⁴C-OFLX and R-(+)-¹⁴C-OFLX at a dose of 20mg/kg.

2. Radioactivity of the S-(-)-isomer was eliminated from blood much faster than that of the R-(+)-isomer. Marked differences in pharmacokinetic parameters exist between the enantiomers; the half life and AUC values of R-(+)-OFLX were greater than those of S-(-)-OFLX. Enantiomeric differences were also seen in the excretion of radioactivity, especially in biliary excretion.

3. 31.3 and 7.4% dose were excreted in the 8?h bile as ester glucuronides after oral administration of S-(-)- and R-(+)-OFLX, respectively. The enantiomeric difference in biliary excretion may be caused by stereoselective glucuronidation of S-(-)-OFLX to the ester glucuronide.

4. The metabolite pattern in serum and urine showed that the ester glucuronide of S-(-)-OFLX was more predominant than that of R-(+)-OFLX.

5. The stereoselective ester glucuronidation of the S-(-)-isomer in rats may induce significant differences in the pharmacokinetic parameters of S-(-)- and R-(+)-OFLX.     

Disposition of Orally and Intravenously Administered Methyltetrahydrofuran in Rats and Mice

The disposition of [¹⁴C]methyltetrahydrofuran (¹⁴C-MTHF) in rats and mice was determined by following changes in the radioactivity in tissue and excreta with time after dosing. MTHF administered orally (1, 10, or 100 mg/kg) or intravenously (1 mg/kg) to either rats or mice was rapidly metabolized and excreted with <8% (mice) or 8–22% (rats) of the dose remaining in the body after 24 h (1 and 10 mg/kg doses) or 72 h (100 mg/kg dose). Based on recovery of radioactivity in excreta (other than feces) and tissues (other than the gastrointestinal [GI] tract), absorption of orally administered MTHF was essentially complete (93–100%). There were no overt signs of toxicity observed at any dose studied. The major route of excretion in mice was in urine followed by exhaled CO₂. In rats the major route of excretion was exhaled CO₂ followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose-dependent in both species; at lower doses exhaled VOC represented 1–5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOCs exhaled at the high dose indicated that the increase was due to exhalation of the parent compound, ¹⁴C-MTHF. Analysis of urine showed three highly polar peaks in the mouse urine and two polar peaks in the rat urine. Because the ¹⁴C label in MTHF was in the methyl group, the polar metabolites were considered likely due to the one-carbon unit getting into the metabolic pool and labeling intermediate dietary metabolites.     

中药补肾方对肾性骨营养不良大鼠肾功能的影响

目的:观察自拟中药补肾方对肾性骨营养不良(ROD)大鼠肾功能的影响。方法:采用5/6肾切除法建立肾功能衰竭大鼠模型,随机分为中药补肾方高剂量组、低剂量组、阳性对照组(骨化三醇)、模型组、假手术组(n=10)。灌胃给药12周,各组取血清测定生化指标,取胫骨测定骨密度,并于光镜下观察病理改变。结果:中药补肾方能够影响ROD大鼠血清钙和碱性磷酸酶水平,改善肾功能,减轻骨组织病理改变,通过整体作用延缓ROD的发生和发展。结论:中药补肾方对ROD大鼠有防治作用。     

Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats

Tofacitinib, a Janus kinase 1 and 3 inhibitor, is mainly metabolized by CYP3A1/2 and CYP2C11 in the liver. The drug has been approved for the chronic treatment of severe ulcerative colitis, a chronic inflammatory bowel disease. This study investigated the pharmacokinetics of tofacitinib in rats with dextran sulfate sodium (DSS)-induced ulcerative colitis. After 1-min of intravenous infusion of tofacitinib (10 mg/kg), the area under the plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib significantly increased by 92.3%. The time-averaged total body clearance decreased significantly by 47.7% in DSS rats compared with control rats. After the oral administration of tofacitinib (20 mg/kg), the AUC increased by 85.5% in DSS rats. These results could be due to decreased intrinsic clearance of the drug caused by the reduction of CYP3A1/2 and CYP2C11 in the liver and intestine of DSS rats. In conclusion, ulcerative colitis inhibited CYP3A1/2 and CYP2C11 in the liver and intestines of DSS rats and slowed the metabolism of tofacitinib, resulting in increased plasma concentrations of tofacitinib in DSS rats.