Circadian Changes in the Pharmacokinetics and Pharmacodynamics of Azosemide in Rats

The circadian changes in the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg^?1) to rats at 1000 or 2200 h. After intravenous administration of azosemide the percentage of the dose excreted in 8-h urine as unchanged azosemide was significantly higher in the 1000 h group than in the 2200 h group (41.7 compared with 28.9%) and this resulted in a significant increase in 8-h urine output (84.7 compared with 36.6 mL/100 g). After intravenous administration the time-averaged renal clearance (CL_R) of azosemide was significantly faster (2.86 compared with 1.76 mL min^?1 kg^?1) and urinary excretion of sodium (46.4 compared with 25.9 mmol/100 g) and chloride (35.6 compared with 18.8 mmol/100 g) increased significantly in the 1000 h group. However, after oral administration, the percentages of oral dose of azosemide excreted in 8-h urine as unchanged azosemide were significantly higher (1.88 compared with 0.67%) and the CL_R of azosemide was significantly faster (3.64 compared with 0.79 mL min^?1 kg^?1) in the 2200 h group. This could be at least partly because of increased absorption of azosemide from the gastrointestinal tract in the 2200 h group; the percentages of oral dose of azosemide recovered from the gastrointestinal tract in 8 h as unchanged azosemide was significantly smaller (5.7 compared with 13.2%) in the 2200 h group. The pharmacodynamic parameters of azosemide were not significantly different after oral administration of the drug to both groups of rats. If these data could be extrapolated to man, the intravenous dose of azosemide could be modified on the basis of circadian time.     

Pharmacokinetics and Pharmacodynamics of Azosemide after Intravenous and Oral Administration to Rats with Alloxan-induced Diabetes Mellitus

Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs used to treat the disease, the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg^?1) to control and alloxan-induced diabetes mellitus rats (AIDRs). After intravenous administration of azosemide to the AIDRs, the area under the plasma concentration-time curve (AUC) increased considerably (3120 compared with 2520 μg min mL^?1; P < 0.135) and the total body clearance decreased considerably (3.20 compared with 3.96 mL min^?1 kg^?1; P < 0.0593). The considerable reduction in time-averaged total body clearance in the AIDRs was a result of the significant decrease in renal clearance (1.01 compared with 1.55 mL min^?1 kg^?1) in the AIDRs, the non-renal clearance being comparable between the two groups of rats. After intravenous administration, the 8-h urinary excretion of azosemide (29.5 compared with 40% of intravenous dose; P < 0.0883) and one of its metabolites, M1 (2.15 compared with 2.60% of intravenous dose, expressed in terms of azosemide; P < 0.05) decreased in the AIDRs because of the impaired kidney function. The diuretic, natriuretic, kaliuretic and chloruretic efficiencies increased significantly in the AIDRs. After oral administration of azosemide, AUC decreased significantly in the AIDRs (115 compared with 215 μg min mL^?1) possibly because of the reduced gastrointestinal absorption of azosemide in the AIDRs. After oral administration of azosemide, the 8-h urine output decreased significantly in the AIDRs (9.32 compared with 16.1 mL per 100 g body weight) because of the significantly reduced 8-h urinary excretion of azosemide (3.00 compared with 9.14% of oral dose). After both intravenous and oral administration some pharmacokinetic and pharmacodynamic parameters of azosemide were significantly different in AIDRs.     

Pharmacokinetics of SDZ 64-412, a novel antiasthmatic agent,following intravenous,oral, and inhalation dosing in the rat

The pharmacokinetics of SDZ 64–412, an antiasthmatic agent, were investigated following intravenous, oral, and inhalation dosing in rats. ¹⁴C-SDZ 64–412 was administered intravenously (2.75 mg kg^?1) and orally (5.5 mg kg^?1, 110 mg kg^?1), whereas non-radiolabeled drug (5.04 mg kg^?1) was administered using nose-only inhalation chambers. Radioactivity and parent drug concentrations in blood, lung, and excreta were determined at designated times post-dose. SDZ 64–412 was rapidly and extensively (～80%) absorbed following both oral doses, although absorption appeared to be prolonged with increasing dose. The absorbed drug was shown to undergo extensive and saturable first-pass metabolism. The bioavailability of the parent drug, calculated by dose-normalized AUC and deconvolution methods, was only 10–15% from the low dose, but increased to ～40% following the high dose. Following inhalation dosing, SDZ 64–412 concentrations in blood and lungs increased rapidly, and did not decline immediately after termination of dosing. The inhalation dose yielded a bioavailability of ～40%, and AUC of the drug in lungs was approximately 25 times greater than in blood. In general, SDZ 64–412 was extensively distributed and rapidly eliminated from the systemic circulation. Biliary excretion was the predominant route of radioactivity excretion. The present findings suggest that inhalation administration provides a viable means of delivery of SDZ 64–412.     

The Anticonvulsant FCE 26743 is a Selective and Short-acting MAO-B Inhibitor Devoid of Inducing Properties towards Cytochrome P450-dependent Testosterone Hydroxylation in Mice and Rats

Abstract— The effects of the potent anticonvulsant FCE 26743 ((S)-2-(4-(3-fluorobenzyloxy)benzylamino)propionamide) on monoamine oxidase (MAO) activity were measured in-vitro and ex-vivo using rat tissue homogenates. In-vitro, FCE 26743 showed potent and selective inhibitory properties towards liver MAO-B, with IC50 values about 10^?7 m for MAO-B and higher than 10^?5 m for MAO-A. When determined ex-vivo in brain, the ED50 value for the inhibition of MAO-B was 1·1 mg kg^?1 (p.o.) 1 h post-dosing, whereas MAO-A remained virtually unaffected after administration of 60 mg kg^?1. Similar effects were seen in liver. Following oral administration of 5 mg kg^?1 FCE 26743 to rats, brain MAO-B inhibition was 79% after 1 h and 13% after 24 h, indicating that FCE 26743 behaves as a short-acting MAO-B inhibitor. The ability of FCE 26743 to act as a MAO substrate was assessed in mice by measuring the urinary excretion of alaninamide, a potential metabolite of FCE 26743 which would result from the action of MAO. No alaninamide was detectable in the 0–8 h urines after administration of a 119 mg kg^?1 dose, suggesting that FCE 26743 is not, or only to a small degree, a substrate of MAO. The effects of FCE 26743 on cytochrome P450 enzymes involved in testosterone hydroxylation were determined in rats after repeated administration. No induction of the cytochrome P450 system was noted.     

Pharmacokinetics and Brain Distribution of Magnolol in the Rat after Intravenous Bolus Injection

The pharmacokinetics of magnolol in rats was studied after 2, 5, or 10 mg kg^?1 intravenous bolus injection. Plasma concentration-time profiles of magnolol were fitted by a two-compartment open model. There were no significant differences in the elimination half-life, the total body clearance, steady-state volume of distribution, or mean residence time. The area under the plasma-time curve and area under the moment-time curve of magnolol appears to increase proportionally from a dose of 2 to 10 mg kg^?1. These results suggest that magnolol possesses linear pharmacokinetics. Notwithstanding, brain concentration of magnolol showed no significant difference among various regions (cerebral cortex, olfactory bulb, hippocampus, striatum, cerebellum, brain stem and rest of brain) after 10 min of magnolol (5 mg kg^?1 i.v.) administration, the mean brain drug concentration was approximately fourfold that of magnolol in plasma.     

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.     

Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor,KNI-272, in rats after intravenous administration

The pharmacokinetic (PK) characteristics of KNI-272, a potent and selective HIV-1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were examined. After IV administration of 10.0 mg kg^?1 KNI-272, the mean terminal elimination half-life, t_1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CL_tot, was 15.1 ± 1.2 mL min^?1 and the distribution volume at steady state, V_d,ss, was 3790±280 mL kg^?1. On the other hand, after 1.0mg kg^?1 IV administration, t_d,ss, was 3.04±0.11 h, CL_tot was 15.9±0.2mL min^?1, and V_d,ss was 6950±600 mL kg^?1. The PK parameters of KNI-272 after IV administration showed that the disposition of KNI-272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg^?1. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL^?1, 0.888 ± 0.008 μg mL^?1, and 0.470±0.55 μg mL^?1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg^?1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg^?1 dose, respectively. The renal clearance (CL_R) and the biliary clearance (CL_B) were calculated to be 0.191 and 0.256mL min^?1 for 1.0mg kg^?1, and 0.0248 and 0.215 mL min^?1 for 10.0 mg kg^?1, respectively. When comparing these values with the CL_tot values, the urinary and biliary excretion of KNI-272 are minor disposition routes.     

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate in rats, dogs and monkeys

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) were studied in rats, dogs and monkeys after administration of [14C]-MN-1695. MN-1695 was found to be well absorbed from the small intestine after oral administration in all species examined. Plasma level of unchanged MN-1695 reached a maximum at 1 to 4 h after oral administration of [14C]-MN-1695 in rats, dogs and monkeys. The mean elimination half-life of unchanged MN-1695 from plasma was about 3, 4 and 50 h in rats, dogs and monkeys, respectively. Tissue levels of radioactivity after oral administration of [14C]-MN-1695 in rats indicated that [14C]-MN-1695 was distributed throughout the body and the radioactivity in tissues disappeared with a rate similar to that in plasma. A stomach autoradiogram after intravenous administration of [14C]-MN-1695 in the rat revealed the radioactivity localized in the gastric mucosa where MN-1695 was assumed to exert its pharmacological activity. In pregnant rats, [14C]-MN-1695 was distributed to the fetus with levels similar to maternal blood levels. After oral administration of [14C]-MN-1695 in rats, 39 to 46% of the dose was excreted into the urine and 50 to 63% of the dose into the feces, within 96 h. In dogs, about 40% of the dose was excreted into the urine and about 50% of the dose into the feces, within 6 days after oral administration. In monkeys, within 14 days after oral administration, about 60 and 30% of the dose were excreted into the urine and feces, respectively, and the main excretion route was the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-Dependent Intestinal Absorption and Significant Intestinal Excretion (Exsorption) of the β-Blocker Pafenolol in the Rat

The elimination of [³H]pafenolol and metabolites was investigated in fasted and fed rats. Separate groups received intravenous doses (0.3 and 3.0 µmol/kg) and oral doses (1 and 25 µmol/kg). After iv administration of pafenolol, the excretion of unchanged drug into urine and feces was about 50 and 25–30% of the given dose, respectively. The predominating mechanism for the excretion of pafenolol into feces was intestinal excretion (exsorption) directly from blood into gut lumen, since only about 3% of a given iv dose was recovered as pafenolol in the bile. When the oral dose was raised from 1 to 25 µmol/kg, the mean (±SD) bioavailability, calculated from urine data, increased from 14 ± 9 to 30 ± 11% (P < 0.05) in the starved rats and from 14 ± 3 to 16 ± 3% in the fed animals. In parallel, the fraction absorbed from the gut (f _a) increased from 19 ± 9 to 31 ± 10% in the starved rats and from 16 ± 4 to 19 ± 5% in the fed animals, respectively. This indicates that the low bioavailability is due primarily to poor intestinal uptake.     

Zur Pharmakokinetik von Dimetacrin bei der Ratte

Phamacokinetics of Dimetacrine in Rats The pharmacokinetics of the tricyclic antidepressant drug [N-¹⁴CH₃]-dimetacrine were studied in male rats. Following oral administration the drug is completely absorbed and rapidly equilibrated between plasma and the tissues. The main route of elimination is the excretion of polar metabolites with the feces while renal elimination is less important. This is in contrast with the elimination kinetics of the structurally related drug imipramine. Following excretion with the bile, different rates of reabsorption from the intestine can be demonstrated for the two drugs.     

Animal pharmacokinetics of inogatran,a low-molecular-weight thrombin inhibitor with potential use as an antithrombotic drug

Pharmacokinetics, excretion, and metabolism of inogatran, a low-molecular-weight thrombin inhibitor, were studied in the rat, dog, and cynomolgus monkey. After intravenous administration the half-life was short in all three animal species, due to a small volume of distribution and a relatively high clearance. At doses of 0.1–5 μmol kg⁻¹, the mean residence time was about 10 min in the rat, 35 min in the dog, and 20 min in the cynomolgus monkey. The oral bioavailability of inogatran was incomplete, presumably due to a low membrane permeability, and dose dependent. The bioavailability was 4.8% at 20 μmol kg⁻¹ and 32–51% at 500 μmol kg⁻¹ in rats, 14% at 10 μmol kg⁻¹ and 34–44% at 150 μmol kg⁻¹ in dogs, and 2.1% at 1 μmol kg⁻¹ in cynomolgus monkeys. The radioactivity excreted in urine and faeces was predominantly unchanged inogatran. After intravenous administration the percentage of the radioactivity recovered in faeces was about equal to or higher than the urinary recovery, which indicates biliary excretion of inogatran. After oral dosing, most of the dose was excreted in faeces, as expected from the estimates of oral bioavailability. The plasma protein binding of inogatran in rat, dog, and human plasma, was 20–28%. The blood–plasma concentration ratio was 0.39–0.56, indicating limited distribution into red blood cells. © 1998 John Wiley & Sons, Ltd.     

Excretion and metabolism of DA-7867, a new oxazolidinone, in rats

Almost negligible hepatic metabolism (minor role of liver for the metabolism) and extensive urinary and fecal excretion of DA-7867 were investigated after intravenous administration at a dose of 10 mg/kg to rats. Pharmacokinetic parameters, especially nonrenal clearances of DA-7867, were very similar between control rats and rats pretreated with SKF 525-A, a nonspecific inhibitor of CYP isozymes, in rats. Similar results were also obtained between control rats and rats with liver cirrhosis induced by dimethylnitrosamine. Hepatic first-pass effect of DA-7867 was almost negligible in rats; the areas under the plasma concentration-time curve from time zero to time infinity of DA-7867 were not significantly different between intravenous and intraportal administration. The above data indicated that liver had almost negligible metabolic activity for DA-7867 in rats. Since metabolism of DA-7867 was not considerable in rats, urinary and fecal excretion of the drug was measured for up to 14 days in ten rats. Fecal excretion was the major route for elimination of DA-7867 in rats; approximately 85.0% of intravenous dose of DA-7867 at 10 mg/kg was recovered from urine (17.0% of intravenous dose), feces (64.0% of intravenous dose), washings of the metabolic cage (3.16% of intravenous dose), and entire gastrointestinal tract (0.421% of intravenous dose).     

Pharmacokinetics,metabolism and excretion of an inhibitor of inducible nitric oxide synthase,L-NIL-TA,in dog

1.?The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog.

2.?The dose of [¹⁴C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5?mg?kg^?1), with C_max of radioactivity of 6.45–7.07?μg equivalents?g^?1 occurring at 0.33–0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively.

3.?Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [¹⁴C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%.

4.?Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.     

Metabolism,pharmacokinetics and excretion of the GABAA receptor partial agonist [14C]CP-409,092 in rats

1. The metabolism and excretion of a GABA_A partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [¹⁴C]CP-409,092.

2. The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15?mg kg^?1, respectively, were characterized by high clearance of 169?±?18?ml min^?1 kg^?1, a volume of distribution of 8.99?±?1.46 l kg^?1, and an oral bioavailability of 2.9% ± 3%.

3. Following oral administration of 100?mg kg^?1 [¹⁴C]CP-409,092, the total recovery was 89.1% ± 3.2% for male rats and 89.3% ± 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48?h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces.

4. The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation.

5. The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.

     

Pharmacokinetics of 14C-DMPS (sodium-1,3 14C-2,3-dimercaptopropane-l-sulphonate) in beagle dogs

The pharmacokinetics of labelled DMPS (sodium-1,3 ¹⁴C-2,3-dimercaptopropane-1-sulphonate) have been studied in four beagle dogs following bolus intravenous injection (65-7 μmolkg^?1) and oral administration (197μmol kg^?1). Following intravenous injection the main kinetic parameters were t_1/2 = 43min, V_β = 160 ml kg^?1, and plasma clearance Cl_p = 2.6ml min^?1 kg^?1. Following oral administration ¹⁴C-DMPS is rapidly absorbed with peak concentrations (478 ± 25 umol 1^?1) measured after 30–45 min. About 60 per cent of the oral dose was absorbed. Estimates of t_1/2, V_β, and Cl_p after oral administration were in close agreement with the values obtained in the intravenous study. ¹⁴C-DMPS is eliminated from the body by the kidneys. About 70 per cent of ¹⁴C-DMPS in dog plasma are bound to proteins. Binding is even higher in plasma from rat and man.     

2,3,6,2′,3′,6′-Hexachlorobiphenyl: Distribution,metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 2,3,6,2′,3′,6′-hexachlorobiphenyl (236-HCB) were investigated in beagle dogs and cynomolgus monkeys (Macaca fascicularis). Following a single iv dose of [¹⁴C]236-HCB (0.6 mg/kg) excreta, blood, and tissues were collected at time intervals ranging from 15 min to 15 days for determination of levels of parent compound and its metabolites. Elimination of the parent PCB in the blood of both species was biphasic with a terminal-phase elimination rate constant of 0.23 day^?1 for the dog and 0.15 day^?1 for the monkey. By 24 hr the dog excreted 52% of the dose; 41% in the feces; 11% in the urine. The percentage dose remaining was found largely in liver, muscle, fat, and skin. By 3 days 70% of the dose was excreted. During the first 24 hr the monkey excreted 19% of the dose with about equal amounts appearing in urine and feces. The percentage dose remaining in the body was localized as parent compound in fat (15%) with lesser amounts in skin, muscle, and liver. By 15 days 61% of the dose was excreted, primarily in the feces. In anesthetized dogs 26% of the dose was excreted into the bile within 2 hr, while anesthetized monkeys excreted only 2.4% of the dose by that route. The data present a clear species variation between the dog and the monkey in the rate of metabolism of 236-HCB and its subsequent excretion via the bile.     

Pharmacokinetics of a non-narcotic analgesic,DA-5018, in rats

The pharmacokinetics of a non-narcotic analgesic, DA-5018, were compared after single intravenous (IV), subcutaneous (SC), and oral administrations, and after multiple (seven consecutive days) SC administration to rats. After IV administration of DA-5018, 1, 2, and 5 mg kg⁻¹, the pharmacokinetic parameters of DA-5018 were independent of the dose ranges studied. After oral administration of DA-5018, absorption of the drug from gastrointestinal (GI) tract was fast, but the extent of absolute bioavailability (F) was low; the values were 23.2, 23.0, and 27.3% for 2, 5, and 10 mg kg⁻¹, respectively. After single SC administration of DA-5018, absorption of the drug from the injected site was fast and the extent of absorption was fairly good; the F values were 74.5 and 71.8% for 2 and 5 mg kg⁻¹, respectively. The lower F values after oral administration of DA-5018 to rats could be due to degradation of the drug in rat GI tract and/or considerable first-pass effect. After IV, oral, and SC administration of DA-5018, the drug had a strong affinity to the rat tissues studied as reflected in the greater-than-unity tissue to plasma ratio. After IV, oral, and SC administration of the drug, the biliary and urinary excretion of unchanged DA-5018 were negligible. There was no significant difference in the pharmacokinetics or tissue distribution of DA-5018 between single and multiple SC administration of the drug, 5 mg kg⁻¹, to rats, indicating that there could be no tissue accumulation of the drug after multiple SC administration of the drug to rats. © 1998 John Wiley & Sons, Ltd.     

Effect of the Selective A1 Adenosine Antagonist 8-Cyclopentyl-1,3-dipropylxanthine on Acute Renal Dysfunction Induced by Escherichia coli Endotoxin in Rats

Abstract— The effect of the selective A₁ adenosine antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on Escherichia coli endotoxin-induced acute renal dysfunction was determined in anaesthetized rats. Bolus administration of endotoxin at doses of either 1 or 20 mg kg^?1 evoked decreases in inulin clearance, renal blood flow, urine flow and excretion of sodium, potassium and chloride. The changes in renal function produced by 20 mg kg^?1 endotoxin were more severe than those noted with 1 mg kg^?1 toxin and, by contrast to this lower dose, renal function showed no signs of recovery. Intravenous administration of CPX (0·1 mg kg^?1) elicited a statistically significant, although modest, attenuation of the decline in inulin clearance, renal blood flow, urine output and electrolyte excretion induced by 20 mg kg^?1 endotoxin. By contrast, treatment with 0·1 mg kg^?1 CPX resulted in statistically significant protection against the falls in excretory function evoked by 1 mg kg^?1 endotoxin but not against the reductions in renal blood flow and inulin clearance produced by the lower dose of toxin. These results suggest that adenosine may play a role, albeit not a major one, in the pathophysiology of endotoxaemic acute renal failure.     

Preclinical pharmacokinetics and metabolism of a potent non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase

The disposition of compound A, a potent inhibitor of the hepatitis C virus (HCV) NS5B polymerase, was characterized in animals in support of its selection for further development. Compound A exhibited marked species differences in pharmacokinetics. Plasma clearance was 44?ml?min^?1?kg^?1 in rats, 9?ml?min^?1?kg^?1 in dogs and 16?ml?min^?1?kg^?1 in rhesus monkeys. Oral bioavailability was low in rats (10%) but significantly higher in dogs (52%) and monkeys (26%). Compound A was eliminated primarily by metabolism in rats, with biliary excretion accounting for 30% of its clearance. Metabolism was mainly mediated by cyclohexyl hydroxylation, with N-deethylation and acyl glucuronide formation constituting minor metabolic pathways. Qualitatively, the same metabolites were identified using in vitro systems from all species studied, including humans. The low oral bioavailability of compound A in rats was mostly due to poor intestinal absorption. This conclusion was borne out by the findings that hepatic extraction in the rat was only 30%, intraperitoneal bioavailability was good, and compound A was poorly absorbed from the rat isolated intestinal loop, with no detectable intestinal metabolism. Compound A was not an inhibitor of major human cytochrome P450 enzymes, indicating minimal potential for clinical drug–drug interactions. The metabolic clearance of compound A in rat, dog and monkey hepatocytes correlated with the systemic clearance observed in these species. Since compound A was very stable in human hepatocytes, the results suggest that it will be a low clearance drug in humans.     

长春西汀在大鼠体内的药代动力学及生理处置

大鼠iv本品的时量曲线属二室开放模型。给大鼠iv本品5及10mg·kg^-1后,药物自血浆的清除呈线性动力学。该药给大鼠iv及ig后,体内分布广、消除迅速,原形药可进入脑组织。本品自大鼠尿、粪、胆汁的排出量均很少。