The pharmacokinetics of a new benzamide drug clebopride, in the rat and the dog

After intravenous, intramuscular and oral administration of clebopride in the rat and the dog its apparent volume of distribution is high (1.6-3.2 1 kg-1) and it has a longer biological half-life than metoclopramide in both species. High clearance values and concentrations of metabolites in plasma after oral administration indicate that the drug is subjected to an extensive first pass metabolism in the rat. Thus, clebopride administered orally gives relatively low concentrations in the systemic circulation in rats even though it is rapidly absorbed. The metabolic processes appear to become saturated at high doses which is reflected in dose-dependent kinetics. Linear kinetics were observed in the dog, although enterohepatic recycling could occur.     

Felbamate pharmacokinetics in the rat, rabbit, and dog.

Rats, rabbits, and dogs were given single iv or single and multiple oral doses of felbamate ranging from 1.6-1000 mg/kg. Absorption of oral drug was complete in all species. The mean Cmax increased with dose from 13.9 to 185.9 micrograms/ml in rats, from 19.1 to 161.9 micrograms/ml in rabbits, and from 12.6 to 168.4 micrograms/ml in dogs. The tmax also increased with dose from 1-8 hr in rats, 8-24 hr in rabbits, and 3-7 hr in dogs. The plasma elimination half-life for the drug increased with dose from 2-16.7 hr in rats, 7.2-17.8 hr in rabbits, and 4.1-4.5 hr in dogs. A proportional increase in Cmax with dose was observed in all species up to 300-400 mg/kg doses. A biexponential equation fitted the drug plasma concentration vs. time data well. For multiple oral doses of 50 mg/kg or less, projected and observed steady-state concentrations agreed well. Animals dosed with [14C]felbamate eliminated most of the radioactivity in urine (58-87.7%), less in feces (7-23.7%), with considerable amounts in the bile. In rats, radioactivity was readily distributed into tissues and crossed the placenta and blood-brain barrier, but no accumulation in any tissue was observed. The volume of distribution was 131, 54, and 72% of body weight for rats, rabbits, and dogs, respectively. Binding of drug to rat, rabbit, and dog plasma proteins ranged from 22.4-35.9%. The overall plasma clearance of the drug for rats, rabbits, and dogs was 327, 52, and 108 ml.h-1.kg-1, respectively. Renal clearance of unchanged drug accounted for an estimated 20-35% and hepatic clearance due to metabolism for 65-80% of the overall clearance.     

Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog

The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.     

The pharmacokinetics and metabolism of Kö 592 in man,dog and rat

Summary Plasma concentration, renal and faecal excretion, absorption and metabolism of the tritiated beta-adrenergic blocker Kö 592 were studied in man, dog and rat. The substance was absorbed to an extent of 90–100% in all species (rat within 30 min, dog within 80 min, man within 120 min). The half-life of radio-activity in the plasma was 3 h in man and dog, in the rat blood 11 h. Excretion is almost complete within the first 12 h in man and dog. While 10–20% of the substance appears in the faeces in rats, elimination in the dog and man is almost exclusively renal. Kö 592 is completely metabolized. The metabolites were isolated from urine and identified by mass spectrometry. With individual variations, 31% of the metabolites of man and dog were present as methylphenoxy lactic acid, 20% as p-hydroxy-Kö 592 and 50% as conjugates. Man conjugates only with glucuronic acid, the dog conjugates 50% with sulphate and 50% with glucuronide.     

The pharmacokinetics of a new benzamide drug,clebopride, in the rat and the dog

After intravenous, intramuscular and oral administration of clebopride in the rat and the dog its apparent volume of distribution is high (1·6–3·2 1 kg^?1) and it has a longer biological half-life than metoclopramide in both species. High clearance values and concentrations of metabolites in plasma after oral administration indicate that the drug is subjected to an extensive first pass metabolism in the rat. Thus, clebopride administered orally gives relatively low concentrations in the systemic circulation in rats even though it is rapidly absorbed. The metabolic processes appear to become saturated at high doses which is reflected in dose-dependent kinetics. Linear kinetics were observed in the dog, although enterohepatic recycling could occur.     

The pharmacokinetics and absolute bioavailability of selegiline in the dog

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. Currently no pharmacokinetic data are available for selegiline in the literature, mainly due to lack of analytical methods that can measure concentrations below 10 ng mL^?1 in plasma. A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to measure selegiline in plasma as low as 0.25 ng mL^?1. The pharmacokinetics of selegiline were investigated following intravenous and oral administration to four female mongrel dogs. Each dog received 1 mg kg^?1 selegiline in solution via gavage or by an intravenous route separated by one week. The mean terminal half-life, volume of distribution of the central compartment, and systemic clearance of selegiline were 60.24 ± 9.56 min, 6.56 ± 0.56 L kg^?1, and 159.91 ± 19.28 mL min^?1 kg^?1, respectively. After oral administration selegiline appeared to be absorbed rapidly with a t_max and C_max of 25 ± 5.8 min and 5.2 ± 1.36 ng mL^?1, respectively. The absolute bioavailability of selegiline in the dog was 8.51 ± 3.31%.     

Metabolism, disposition, and pharmacokinetics of tracazolate in rat and dog

The metabolism, disposition, and pharmacokinetics of tracazolate, (4-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester), a novel anxiolytic agent, were studied in rat and dog following single oral and iv doses. Although tracazolate exhibits very good absorption (greater than 80%) in both species, it is extensively metabolized, accounting for low bioavailability. Excretion of 14C was rapid, with the kidney being the major organ of excretion. Tracazolate was not detected in the urine after iv doses even though measurable levels were found in blood, suggesting reabsorption of the compound by the renal tubules. The logarithm of the blood drug concentration vs. time data for both species was best described by a three-compartment open model. Mean t1/2 (beta) for tracazolate in the rat and dog were 14 and 10 hr, respectively. The distribution of radioactivity in rats showed that the concentrations of 14C and 14C-tracazolate were greater in tissues than in blood. Tracazolate was the predominant radioactive compound in brain during the first 6 hr and in fat for 96 hr. The extent and decay of tracazolate in fat strongly suggest that this tissue contributes significantly towards the equilibrium of drug between "deep body compartments" and blood. The major metabolite in blood was de-esterified tracazolate (ICI-US 7773) and in brain the gamma-ketotracazolate (ICI-US 10052).     

The pharmacokinetics of etretinate and its metabolites in the dog

The pharmacokinetics and disposition of etretinate (ET) and its metabolites, etretin (ETA) and isoetretin (c-ETA), were studied in the dog. Administration of ET, ETA, and c-ETA by several routes of administration allowed the use of a physiologically based model to assess the relative contributions of absorption and presystemic metabolism to the oral bioavailability of these compounds. The large Vdss (214 +/- 228 liters/kg) of ET and terminal half-life of greater than 300 hr indicated the wide distribution and prolonged storage of ET in the tissues. After a dose of ET, its two metabolites, ETA and c-ETA, were also detectable in the plasma. The oral bioavailability of ET in the dog was 52.5% with 95.4% of the dose available for absorption from the gut lumen. Of the ET that was absorbed from the gut lumen, 26.4% and 25.5% was removed by the gut wall and liver, respectively. ETA was found to be a formation rate-limited metabolite of ET. Although the oral bioavailability of ETA could not be determined because its administration was not possible by the iv route, it appeared that only 16% of an orally administered dose entered the portal circulation from the gut. c-ETA was detected after administration of either ET or ETA. ETA and c-ETA were shown to be interconvertible metabolites, but the equilibrium of the conversion between c-ETA and ETA favored the formation of ETA. The oral bioavailability of c-ETA was 42.4%, but the liver showed little metabolic activity toward c-ETA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioanalyses and pharmacokinetics of nafronyl in the dog

Improved specific and sensitive reverse-phase HPLC assays of nafronyl (I) and its acidic metabolite and hydrolysis product (II) in biological fluids were developed with sensitivities of 3-6 ng/mL using fluorometric detection with 225 nm excitation and 330 nm emission wavelengths. There were no significant differences in the stabilities and assays of I and II in plasma obtained using heparin, citrate phosphate dextrose solution, EDTA, citrate, or oxalate as anticoagulant. Inordinately high membrane binding did not permit the quantification of the high plasma protein binding of I by ultrafiltration; its instability precluded the use of equilibrium dialysis. Plasma protein binding of II by ultrafiltration was 76.4% and was not concentration dependent. The apparent red blood cell-plasma partition coefficients for I and II were 2.00 and 0.49, respectively, with almost all anticoagulants; the red blood cell-plasma water partition coefficient for II was 2.08 when corrected for plasma protein binding. Thus, both I and II had erythrocyte binding sites in addition to simple volume partitioning. Only heparin-treated blood gave anomalously low erythrocyte-plasma partition coefficients, indicating that heparin inhibited the partitioning of I and II into red blood cells from plasma water. The total body clearance of nafronyl (I) referenced to total plasma concentration [1295 +/- 65 (SEM) mL/min] was dose independent (35-70-mg range) and showed biphasic plasma half-lives (intravenous) of 12 and 100 min. Only 34% of the nafronyl appears as systemically circulating II in the plasma. Apparent volumes of distribution similarly referenced were 39.8 and 163 L for the central compartment and total body, respectively. Renal clearances referenced to total plasma concentration were 8.3 and 0.18 mL/m for I and II, respectively. The respective total urinary excretions of I, II, and the glucuronide of II (III) were 0.48, 0.021, and 0.32% of the administered intravenous doses. The respective total urinary excretions of I, II, and III for a bile-cannulated dog were 0.005, 0.16, and 0.40%. The total body clearance of intravenously administered II was 225 mL/min, with a renal clearance of 0.057 mL/min referenced to total plasma concentration. The respective total urinary excretions of II and III were 0.027 and 0.44% of the intravenous dose of II. Respective plasma half-lives of II (intravenous) were 2.5, 10.9, and 225 min. The apparent volume of distribution referenced to total plasma concentration was 2.2 L (9.1 L referenced to plasma water concentration). The apparent overall volume of distribution referenced to plasma concentration was 73 L.(ABSTRACT TRUNCATED AT 400 WORDS)     

The pharmacokinetics of penicillamine in a female mongrel dog

The pharmacokinetic parameters of D-penicillamine were investigated by administering four intravenous bolus doses, four oral doses, and six constant rate intravenous infusions to a female mongrel dog at dosages comparable to 250, 500, 750, and 1000 mg in man. The pharmacokinetics of D-penicillamine demonstrated nonlinearity in the dog. There was more than proportional increase in the area under the whole blood concentration curve for an increase in the bolus intravenous dose. The steady state whole blood, plasma, and packed cell levels of penicillamine were increased more than proportionately for an increase in the intravenous infusion rate. Total body clearance of penicillamine was decreased by increasing the dose or the infusion rate of penicillamine. Correspondingly, the estimated half-life of unchanged penicillamine in the whole blood was decreased for increased intravenous bolus doses. The renal clearance of penicillamine was nonlinear, decreasing with time during the bolus experiments and increasing at higher infusion rates. The nonrenal clearance was decreased at higher infusion rates, suggesting that a saturable nonrenal elimination process exists for penicillamine in the dog. The nonlinearities that were observed in the dog, if also present in man, may be responsible in part for the dose related side effects reported clinically for penicillamine.1980–1981 American Foundation for Pharmaceutical Education Manufacturing and Industrial Pharmacy FellowThis research was supported in part by a National Institutes of Health Grant (AM-20557-02-51).     

The pharmacokinetics and metabolism of idazoxan in the rat

1. [2'-14C]Idazoxan was rapidly and completely absorbed after its oral administration to rats. 2. After administration of either [2'-14C] or [6,7-3H]idazoxan, radioactivity was taken up by a wide range of tissues and became localized, especially in the organs of metabolism and excretion. Quantitative distribution patterns were route-dependent such that oral dosing resulted in lower radioactivity concentrations in all tissues apart from liver. 3. Clearance of idazoxan (94-144 ml/min per kg) was due mostly to metabolism and was independent of dose. Oral bioavailability in male rats at low oral doses of idazoxan (10 mg/kg) was about 1%, but increased with increasing dose to 23% at 100 mg/kg. Oral bioavailability in female rats was considerably higher than in male rats, at all doses studied. Brain idazoxan levels were in equilibrium with those in plasma, but ten-fold higher. 4. Elimination of radioactivity after administration of 14C-idazoxan was via the urine and the faeces (about 75% and 20% of dose respectively) and occurred essentially in the 24 h period immediately after dosing. By 96 h after dosing, elimination was virtually complete, with less than 0.5% dose remaining in the carcasses. 5. Biotransformation was by hydroxylation at positions 6 and 7 to form phenolic metabolites, which were excreted as glucuronide and sulphate metabolites in urine, but unconjugated in faeces. Other minor metabolic routes were 5-hydroxylation or oxidative degradation of the imidazoline ring, but these pathways were of quantitatively minor importance in the rat.     

The disposition and pharmacokinetics of ketoconazole in the rat

The disposition, biliary excretion, and pharmacokinetics of ketoconazole in Sprague-Dawley rats were determined after intravenous administration. Greater than 80% of the radioactivity after a 5 mg/kg iv dose of 3H-ketoconazole was excreted in the feces. Urinary excretion was essentially complete after 48 hr; however, fecal excretion was prolonged over a 7-day period. Biliary excretion of radioactivity averaged 54.3 +/- 18.0% of the dose over a 7.5-8-hr period in pentobarbital-anesthesized rats. The possibility of enterohepatic recirculation was examined using a linked rat technique. Less than 2% of the radioactivity was found in the recipient bile over 9-12 hr. In eight male rats, the plasma pharmacokinetics of ketoconazole, as determined by an HPLC assay with fluorescence detection, were as follows: VD = 655 +/- 91 ml/kg, Cl = 14.4 +/- 5.1 ml/min/kg, and t 1/2 = 35.0 +/- 12.3 min. Three of the rats were given an additional oral dose to determine absolute bioavailability. The time to peak was 30-60 min, and the bioavailability was 35.8 +/- 3.55%. Previous studies have indicated that ketoconazole is well absorbed in rats; therefore, the poor bioavailability is probably due to first pass metabolism. The prolonged fecal excretion of radioactivity from an intravenous dose was probably caused by slow elimination of ketoconazole metabolites.     

The pharmacokinetics of metoclopramide in man with observations in the dog.

1 The pharmacokinetics of metoclopramide have been studied in eight normal male volunteers. 2 The mean plasma beta half-life was 156.7 min after i.v. administration of 10 mg metoclopramide. 3 After oral dosing of 10 mg the mean half-life was 196.6 min and after 20 mg 317.5 min (P less than 0.05). 4 Bioavailability of a 10 mg oral dose of metoclopramide varied between 32 and 97%. 5 A major urinary metabolite was metoclopramide-N-4-sulphate and the amounts of conjugates appearing in urine to 24 h correlated significantly with the bioavailability. 6 In the dog the metabolic fate of metoclopramide is different to man with conjugation being a minor metabolic pathway. The half-life in the dog does not appear to be dose dependent. 7 The wide differences in bioavailability of metoclopramide in man may contribute to the unpredictable occurrence of side effects.     

The pharmacokinetics of orally administered S-carboxymethyl-l-cysteine in the dog,calf and sheep

The aim of this study was to investigate the feasibility of employing S-carboxymethyl-l-cysteine as a treatment of chronic obstructive pulmonary disease in dogs. To this end the pharmacokinetic parameters of orally administered S-carboxymethyl-l-cysteine were determined in the dog, cow and sheep. Six healthy beagle dogs, six endogenous Greek sheep and four Holstein Fresian calves were orally dosed with 10 mg/kg body weight of S-carboxymethyl-l-cysteine. No significant differences in T_max and T_1/2 were reported between the species. However, significantly higher AUC_(0–last), 21.56 ± 6.67 μg h ml^?1 and AUC_(0–∞), 21.63 ± 6.68 μg h ml^?1 were seen in the dogs compared to the sheep and calves. The calculated V_D was significantly higher in the sheep (10.4 ± 2.7 L kg^?1) and the calves (3.8 ± 0.7 L kg^?1) compared to the dogs (1.0 ± 0.6 L kg^?1). The rank order of increasing C_L was sheep (3.4 ± 2.7 L h^?1 kg^?1) > calves (2.7 ± 0.4 L h^?1 kg^?1) > dogs (0.5 ± 0.2 L h^?1 kg^?1). The result for the dogs was significantly lower that the calculated C_L for the sheep and calves.All these results indicate that the oral administration of S-carboxymethyl-l-cysteine may be useful during the therapeutic management of chronic obstructive pulmonary disease in dogs.     

The pharmacokinetics of inhaled chlorobenzene in the rat

Male rats were exposed for 8 hr/day to 100, 400, or 700 ppm of [¹⁴C]chlorobenzene vapor for either 1 or 5 days for the purpose of examining the dose dependency of parameters indicative of the toxicity process and the effect of repeated exposure. ¹⁴C burdens in the blood, liver, kidneys, lungs, and fat were measured at 0, 16, and 48 hr after exposure. The labeled material excreted in the urine and expired air was collected for 48 hr. Analysis was performed on both the rates and total amounts eliminated. The mercapturic acid percentage of the urinary metabolities excreted in the first 24 hr was measured. The ¹⁴C burdens of all tissues increased in proportion to increased exposure concentrations, except for adipose tissue burdens, which increased more than 30-fold between 100 and 700 ppm. Respiratory elimination of ¹⁴C also increased disproportionately. The urinary metabolite profile was altered, with a dose-dependent decrease in the mercapturic acid percentage from 68% at 100 ppm to 51% at 700 ppm. changes due to multiple versus single exposures were higher tissue burdens 48 hr after exposure, less total excretion of label, a lesser percentage of the total excreted through respiration, and a change in the rate of respiratory excretion. The dose-dependent changes are postulated to be due to saturation of the metabolic elimination of chlorobenzene. The effect of multiple exposure is apparently some stimulation of metabolism.     

Comparative pharmacokinetics of benzodiazepines in dog and man

The pharmacokinetic parameters disposition half-life, metabolic clearance, volume of distribution, intrinsic clearance of unbound drug, and (distributive tissue volume/unbound fraction in tissue) were compared for 12 benzodiazepines in dog and man. With the exception of volume of distribution, statistically significant correlations were obtained when parameters were plotted on a double logarithmic grid. In general, benzodiazepines were metabolized more rapidly and exhibited greater tissue distribution in dog than in man. The variability in parameters was such, however, as to make extrapolations from one species to another subject to considerable error.