Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers

AIMS: To investigate the tolerability and safety of clevidipine in healthy male volunteers during intravenous infusion at gradually increasing dose rates and to obtain preliminary information on the pharmacokinetics and pharmacodynamic effects of the drug. METHODS: Twenty-five subjects were enrolled in the study and twenty-one of them were included twice, resulting in a total of forty-six study entries encompassing 20 min infusions of clevidipine at target dose rates ranging from 0.12 to 48 nmol min-1 kg-1. Haemodynamic variables and adverse events were recorded throughout the study. Concentrations of clevidipine and its primary metabolite, H 152/81, were followed in whole blood, and the pharmacokinetics were evaluated by non-compartmental and compartmental analysis. An Emax model was fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the corresponding blood concentrations of clevidipine. RESULTS: Clevidipine was administered up to a target dose rate of 48 nmol min-1 kg-1, where a pre-determined escape criterion was reached (HR>120 beats min-1 ) and the study was stopped. The most common adverse events were flush and headache, which can be directly related to the mechanism of action of clevidipine. There was a linear relationship between blood concentration and dose rate in the range studied. The median clearance value determined by non-compartmental analysis was 0.125 l min-1 kg-1. Applying the population approach to the sparse data on clevidipine concentrations, an open two compartment pharmacokinetic model was found to be the best model in describing the disposition of the drug. The population mean clearance value determined by this method was 0.121 l min-1 kg-1, and the volume of distribution at steady state was 0.56 l kg-1. The initial half-life, contributing by more than 80% to the total area under the blood concentration-time curve following i.v. bolus administration, was 1.8 min, and the terminal half-life was 9.5 min. At the highest dose rates, MAP was reduced by approximately 10%, and the HR reached the pre-determined escape criterion for this study (>120 beats min-1 ). CONCLUSIONS: Clevidipine is well tolerated and safe in healthy volunteers at dose rates up to at least 48 nmol min-1 kg-1. The pharmacokinetics are linear over a wide dose range. Clevidipine is a high clearance drug with extremely short half-lives. The effect of clevidipine on the blood pressure was marginal, probably due to a compensatory baroreflex activation in this population of healthy volunteers. A simple Emax model adequately describes the relationship between the pharmacodynamic response (MAP/HR) and the blood concentrations of clevidipine.     

Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion

Objective: To determine the pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in healthy male volunteers following a constant rate infusion. Methods: Eight healthy male volunteers received 1030 nmol · min⁻¹ of clevidipine together with a tracer dose of ³[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing infusion and up to 32 h following termination of the infusion. The excretion of radioactivity in urine and faeces was followed for 7 days. Results: A two-compartment model gave the best fit to the individual clevidipine blood levels, resulting in a mean blood clearance of 0.14 (0.03) l · min⁻¹ · kg⁻¹ and a mean volume of distribution at steady state of 0.6 (0.1) l · kg⁻¹. The initial half-life was 1.6 (0.3) min, and the terminal half-life was 15 (5) min. The maximum concentration of the metabolite H 152/81 was reached 2.2 (1.3) min following termination of the infusion. The mean terminal half-life of the inactive primary metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following termination of the 1 h infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min. Conclusion: Clevidipine is a high clearance drug, which is rapidly metabolized to the corresponding inactive acid. The t_max value of the primary metabolite, and a virtually identical value of the initial half-life and the half-life for elimination from the central compartment, indicate that the initial rapid decline of the post-infusion blood levels is mainly due to elimination rather than distribution. The duration of action of clevidipine is short. Received: 23 September 1998 / Accepted in revised form: 20 November 1998     

In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man.

The objectives of this study were to investigate the protein binding and the in vitro hydrolysis rate of clevidipine and its enantiomers in the rat, dog and man in different biological matrices including blood and plasma from volunteers with deficient pseudocholinesterase activity. The in vitro half-life in blood was 0.6 min (rat), 15.7 min (dog) and 5.8 min in man with normal pseudocholinesterase activity, while the half-life was approximately 9 min in blood from pseudocholinesterase deficient volunteers. The half-life in pseudocholinesterase deficient volunteers was prolonged, although the hydrolysis rates in blood and red blood cells (RBC) were much higher than in plasma, suggesting that esterases located in the RBC are most important in the blood metabolism of clevidipine. A decrease in temperature increased the half-life of clevidipine in blood, whereas dilution of the blood did not affect the in vitro half-life of clevidipine. The albumin concentration affected the hydrolysis rate of clevidipine in RBC suspended with saline. The protein binding of clevidipine and its enantiomers was >99.5% in plasma from all species studied. There was a difference between the free fractions of S- and R-clevidipine in man, 0.43 and 0.32%, respectively, and this stereoselective binding might be the reason for the 10% difference between the in vitro hydrolysis rates of the enantiomers in human blood.     

Circulatory effects and pharmacology of clevidipine, a novel ultra short acting and vascular selective calcium antagonist, in hypertensive humans.

The pharmacokinetics of clevidipine, a potent short-acting vascular-selective calcium antagonist, was investigated during steady state and the postinfusion period in patients with mild to moderate hypertension. Furthermore, the dose-effect and blood concentration-effect relations and the tolerability of the drug were studied. Twenty patients were randomized to clevidipine intravenously at target dose rates of 0.18, 0.91, 2.74, and 5.48 microg/kg/min, respectively, or placebo. Each patient received in random order three infusion rates of clevidipine or placebo during three separate study days. Dose-dependent reduction in blood pressure and a modest increase in heart rate were noted. The extremely high clearance value and the small volume of distribution resulted in short half-lives of clevidipine, 2.2 and 16.8 min, respectively. The blood concentration and dose rate producing half the maximal effect (i.e. EC50 and ED50) were approximately 25 nM and 1.5 microg/kg/min, respectively. There was a linear relation between blood concentration and dose rate in the range studied. Clevidipine was safe and generally well tolerated; one patient was excluded because of adverse events at 2.74 microg/kg/min. In conclusion, clevidipine is a high-clearance calcium antagonist that may become a valuable contribution to the drugs used in conditions in which precise and rapid control of blood pressure is needed.     

Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs.

Gemcitabine, 2'-deoxy-2',2'-difluorocytidine, is a broad spectrum oncolytic compound with antitumor activity in solid tumor models. The pharmacokinetics, metabolism, and disposition of gemcitabine was examined in mice, rats, and dogs. All three species metabolize gemcitabine by deamination to the uracil metabolite. However, deamination in the mouse and dog was more extensive than in the rat. The mouse deaminated gemcitabine rapidly with the plasma concentration maximum of the uracil metabolite of gemcitabine being attained at 15 min postdosing compared with approximately 3 and 6 hr in the dog and rat, respectively. The rapid deamination in the mouse was also reflected in the plasma half-life of the parent compound. The mouse exhibited the shortest plasma half-life, approximately 0.28 hr, contrasted with 2.14 and 1.38 hr half-lives in rat and dog, respectively. Plasma AUC for the uracil metabolite of gemcitabine was 73%, 10.5%, and 315% of that for gemcitabine in the mouse, rat, and dog, respectively. Tissue concentrations of gemcitabine-derived radioactivity in the rat and mouse indicated that gemcitabine was rapidly distributed throughout the body. Half-lives of radioactivity in tissues of both the rat and mouse were relatively short, with the longest tissue half-lives of 5.7 and 3.0 hr, respectively. Plasma protein binding is negligible in all three species. The major route of elimination is via the urine in all three species with 76-86% of the dose excreted in the first 24 hr. The predominant radiolabeled component isolated from urine was gemcitabine in the rat and its uracil metabolite in the mouse and dog.     

Pharmacokinetics, metabolism, and disposition of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine (SK&F 86466) in rats and dogs

The pharmacokinetics and metabolism of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine (SK&F 86466) have been studied in rats and dogs. Using radiolabeled SK&F 86466, it was shown that the compound was completely absorbed from the gastrointestinal tract following oral administration. Most of the administered radioactivity (approximately 80%) was excreted in urine with the remainder excreted in feces via the bile. Very little of the parent compound was excreted unchanged in the urine. The major urinary metabolite, accounting for about 55% of the dose in rat and 35% in dog, was the N-oxide. N-Demethylation also occurs in both species, and in the rat approximately 20% of the dose is metabolized by this route. The plasma concentration vs. time curves following iv administration were analyzed using a two-compartment open model. The distribution phase half-life was 0.24 hr in the rat and 0.37 hr in the dog. In both species the terminal half-life was approximately 2 hr. The volume of distribution at steady state in the rat was 12.1 liters/kg and in the dog was 8.2 liters/kg. About 55% of the drug in plasma was bound to protein in both species so that the volume of distribution of the free drug was 27 liters/kg in the rat and 19 liters/kg in the dog. The clearance of SK&F 86466 from blood was very high in both the dog (56 ml/min/kg) and the rat (191 ml/min/kg). Since less than 1% of the compound was excreted unchanged in urine, the clearance was almost entirely metabolic.(ABSTRACT TRUNCATED AT 250 WORDS)     

Time-dependent cardioprotection with calcium antagonism and experimental studies with clevidipine in ischemic-reperfused pig hearts: part I

Clevidipine is a new ultrashort-acting dihydropyridine calcium antagonist developed for blood pressure regulation during cardiac surgery. When given locally to the ischemic and reperfused myocardium, clevidipine exerts a cardioprotective effect that varies depending on the timing of administration during ischemia. The current study explored the pharmacokinetics of clevidipine when administered locally into the coronary circulation. Pentobarbital-anesthetized pigs were randomly divided into four groups, of which three were subjected to myocardial ischemia through ligation of the left anterior descending coronary artery (LAD) for 15, 35, or 45 minutes (n = 4 in each group). The fourth group (n = 4) was not subjected to LAD occlusion and acted as nonischemic controls. Clevidipine (0.3 nmol/kg per minute) was infused over a period of 5 minutes through a catheter distal to the LAD ligation in the ischemic pigs, or at the corresponding site of the nonligated LAD in the nonischemic pigs. Following release of the LAD ligation, or in the nonligated group following the drug infusion, the pigs were subjected to 60 minutes of reperfusion. Simultaneous blood samples were obtained for analysis of clevidipine from the femoral artery and the coronary vein during reperfusion and during drug infusion in the nonischemic pigs. Blood samples for estimating the in vitro hydrolysis rate both in whole blood and in plasma were also obtained. In nonischemic hearts, clevidipine reached a steady state level in the coronary venous blood of about 30 nM during the infusion. The concentration declined almost to the detection limit (1 nM) within 3 minutes of the end of infusion. The mean blood clearance of clevidipine was calculated to be 0.17 l/min per kilogram, and the estimated half-life was 0.5 minute. In animals subjected to different periods of ischemia, very low levels of clevidipine were detected in the coronary venous blood only during the first 2 minutes of reperfusion. There were no detectable levels in the arterial blood at any time. Blood concentration profiles of clevidipine did not differ with the length of myocardial ischemia. The in vitro half-life in pig blood was 13 minutes, and the corresponding half-life in plasma was 111 minutes. At a dose known to exert cardioprotection when given as an intracoronary injection, the systemic concentration of clevidipine does not reach pharmacologically active levels. Clevidipine has an ultrashort blood half-life, and ischemic duration of up to 45 minutes does not seem to change the cardiac metabolism of this drug. Thus, it represents a pharmacological tool well suited for the study of time windows in cardioprotection. Moreover, considering the possibility of exerting myocardioprotection without any systemic effects, it could be an interesting compound to test in a clinical setting.     

Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control

Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.     

Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension

Purpose

Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion.

Method

Doses of 2, 4, 8, or 16.0?mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0?mg/h and force-titrated in doubling increments every 3?min to target dose, then maintained for 72?h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8?h after termination of infusion, although oral therapy could be restarted at 4?h. Clevidipine blood levels were obtained during infusion and for 1?hour after termination.

Results

Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6?h after termination of the clevidipine infusion. At 8?h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8?h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline.

Conclusion

This study supports the use of up to 72?h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.     

Absorption,distribution, metabolism and excretion of cizolirtine,a new analgesic compound,in rat and dog

1. The pharmacokinetics of cizolirtine citrate, a new analgesic compound, were studied in the rat and dog following single oral and intravenous doses. 2. Absorption of radioactivity was fast and complete regardless of the species, and no dose and food-related differences were found. However, the elimination half-life of unchanged cizolirtine was shorter in rat than in dog. 3. Tissue distribution of total radioactivity in rat differed widely and a high affinity for liver, kidney, gastrointestinal and pigmented tissues was observed. In blood and almost all tissues the highest concentrations were reached at 20 min; beyond that time the decline of radioactivity in most tissues was parallel to that in blood. 4. The percentage of radioactivity excreted in the rat was 68% in urine and 21% in faeces, the latter being apparently due to drug enterohepatic circulation. In the dog, 92 and 4% of the radioactivity was found in urine and faeces respectively. The contribution of renal excretion to cizolirtine elimination was 5% in rat and 20% in dog. Twelve metabolites were detected in rat and six in the dog by radio-hplc analysis of urine.     

Absorption, distribution, metabolism and excretion of cizolirtine, a new analgesic compound, in rat and dog.

1. The pharmacokinetics of cizolirtine citrate, a new analgesic compound, were studied in the rat and dog following single oral and intravenous doses. 2. Absorption of radioactivity was fast and complete regardless of the species, and no dose and food-related differences were found. However, the elimination half-life of unchanged cizolirtine was shorter in rat than in dog. 3. Tissue distribution of total radioactivity in rat differed widely and a high affinity for liver, kidney, gastrointestinal and pigmented tissues was observed. In blood and almost all tissues the highest concentrations were reached at 20 min; beyond that time the decline of radioactivity in most tissues was parallel to that in blood. 4. The percentage of radioactivity excreted in the rat was 68% in urine and 21% in faeces, the latter being apparently due to drug enterohepatic circulation. In the dog, 92 and 4% of the radioactivity was found in urine and faeces respectively. The contribution of renal excretion to cizolirtine elimination was <5% in rat and 20% in dog. Twelve metabolites were detected in rat and six in the dog by radio-hplc analysis of urine.     

The pharmacokinetics of bucindolol and its major metabolite in essential hypertension

The pharmacokinetics of bucindolol and its major metabolite, 5-hydroxybucindolol, have been studied in eight patients with mild/moderate hypertension. The mean terminal elimination half-life of bucindolol following acute oral dosing was 8.0 +/- 4.5 h, while the elimination half-life of the metabolite was 0.15 +/- 0.13 h. Because of the large intraindividual variation in the pharmacokinetics of the drug and metabolite, no significant differences in the kinetics following acute or chronic dosing were seen. There was very wide interindividual variability in the pharmacokinetics of bucindolol and 5-hydroxybucindolol, and large interindividual differences in the metabolic profiles as assessed by the areas under drug and metabolite concentration-time curves. This latter observation might be associated with a genetic polymorphism of drug metabolism.     

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 CYP3A12-dependent metabolism of c-kit inhibitor imatinib in dogs

Imatinib is a highly selective tyrosine kinase inhibitor, and is used for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISTs) in humans. The aim of this study is to determine the in vitro and in vivo pharmacokinetics of imatinib in dogs and which cytochrome P450 (CYPs) contribute to its metabolism. Imatinib was administered orally or intravenously to dogs and the time of the peak concentration (T(max)) of imatinib was 4-9 h. The mean half-life was 622 +/- 368 min, and the AUC was 1256 +/- 809 microM * min after oral administration. The range of C0 of intravenously injected dogs was 12-24 microM. The half-life and AUC after intravenous injection were 206 +/- 112 min and 1026 +/- 371 microM * min, respectively. Recombinant system of dog CYP3A12 and CYP2C21 showed that CYP3A12 contributed to the metabolism of imatinib. The inhibition of CYP3A-dependent activity using a rat anti-CYP3A antibody or ketoconazole revealed that CYP3A12 plays a major role in the metabolism of imatinib in dog liver microsomes.     

Deoxyribose analogues of N6-cyclopentyladenosine (CPA): partial agonists at the adenosine A1 receptor in vivo.

1. The purpose of the present study was to quantify the cardiovascular effects of the 2'-, 3'-, 5'-deoxyribose analogues of the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA) in vivo. The blood concentration-effect relationships of the compounds were assessed in individual rats and correlated to their receptor binding characteristics. 2. The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous infusion of 0.80 mg kg (-1) (63 micromol kg(-1)of 2' dCPA. The heart rate (HR) and mean arterial blood pressure (MAP) were monitored continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentration. 3. The relationship between blood concentrations and the reductions in both heart rate and blood pressure were described according to the sigmoidal Emax model. For the bradycardiac effect, the potencies based on free drug concentrations (EC50,u) of 5'dCPA, 3'dCPA, 2'dCPAin blood were 5.9 +/- 1.7, 18 +/- 4 and 260 +/- 70 ng ml (-1) (19 +/- 6, 56 +/- 11 and 830 +/- 210 nM), respectively, and correlated well with the adenosine A1 receptor affinity in vitro. The Emax value of 2'dCPA was significantly less than those of the other compounds, suggesting that this compound may be regarded as a partial agonist when compared to the other analogues. The rank order of the maximal reduction in heart rate of the compounds corresponded well with the order of the GTP-shifts, as determined in vitro. 4. It is concluded that deoxyribose derivatives of CPA may be partial agonists for the adenosine A1 receptor and may serve as tools for further investigation of adenosine receptor partial agonism in vivo.     

Pharmacokinetics and metabolism of mespirenone, a new aldosterone antagonist, in rat and cynomolgus monkey

The pharmacokinetics and metabolism of mespirenone were examined in rat and cynomolgus monkey using the tritiated drug. Following i.v. administration, mespirenone exhibited a short half-life and a high plasma clearance; after oral administration the unchanged compound was not detectable. Thus, mespirenone has to be considered a pro-drug. From rat urine three metabolites were isolated by h.p.l.c. and identified by mass spectra and 1H n.m.r., all having retained the 7 alpha-sulphur substituent as a thiomethyl or a sulphinylmethyl group. The 7 alpha-thiomethyl metabolite had a half-life of six hours in rat plasma and its AUC value was 35% of that for total 3H. As this metabolite has marked anti-aldosterone activity, it is an active metabolite that contributes to the pharmacological effect of mespirenone.     

The metabolism of talampicillin in rat, dog and man

1. After administration of [phthalidyl-14C] talampicillin (Talpen) to rat, dog and man, radioactivity was excreted mainly in the urine (90%, 86% and 98% in rat, dog and man respectively). 2. After administration of [ampicillin-14C] talampicillin, radioactivity was excreted in the urine of rats and dogs to a lesser extent (35% in both species) and only a small proportion of the dose was excreted in the bile (6% in rats, less than 0.1% in dogs). 3. The pattern of radiometabolites was very similar in extracts of the urines of radiometabolites was very similar in extracts of the urines of rat, dog and man dosed orally with [phthalidyl-14C]talampicillin. The major metabolite was 2-hydroxymethylbenzoic acid. 4. Unchanged talampicillin was present in the hepatic portal vein blood of dog and thus reached the liver, whereas in rat, no parent compound could be detected in portal vein blood. This result may help to explain differences in toxicity of the compound in rat and dog. 5. Studies in vitro showed that the intestinal wall is an important site of hydrolysis of talampicillin in rat and dog.     

The disposition, metabolism, and pharmacokinetics of a selective metabotropic glutamate receptor agonist in rats and dogs.

Compound LY354740 [(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid], an analog of glutamic acid, is a selective group 2 metabotropic glutamate receptor agonist in clinical development for the treatment of anxiety. Studies have been conducted to characterize the absorption, disposition, metabolism, and excretion of LY354740 in rats and dogs after intravenous bolus or oral administration. Plasma concentrations of LY354740 were measured using a validated gas chromatography/mass spectrometry assay. In rats, LY354740 demonstrated linear pharmacokinetics after oral administration from 30 to 1000 mg/kg. The oral bioavailability of LY354740 was approximately 10% in rats and 45% in dogs. In the dog, food decreased the mean area under the plasma concentration-time curve value by approximately 34%, hence, decreasing the oral bioavailability of the compound. Excretion studies in both rats and dogs indicate that the absorbed drug is primarily eliminated via renal excretion. In addition, tissue distribution in rats showed that the highest levels of radioactivity were in the kidney and gastrointestinal tract, which is consistent with the excretion studies. Metabolism of LY354740 was evaluated in vitro using rat and dog liver microsomes and rat liver slices. In addition, urine and fecal samples from rat and dog excretion studies were profiled using HPLC with radio-detection. These evaluations indicated that neither rats nor dogs metabolized LY354740. In summary, LY354740 is poorly absorbed in rats, moderately absorbed in dogs, and rapidly excreted as unchanged drug in the urine.     

Cyclosporine pharmacokinetics in rats and interspecies comparison in dogs, rabbits, rats, and humans

The pharmacokinetics of cyclosporine, a potent immunosuppressive agent, are described for rats given 5 mg/kg iv, measuring blood concentrations by a specific HPLC method. Cyclosporine followed first-order kinetics and blood concentrations vs. time data were adequately described by a three-compartment open model system. The mean half-life of the lambda 1 phase was 0.11 hr, that of the lambda 2 phase was 1.82 hr, and the half-life of the estimated lambda 3 phase was 23.79 hr. The mean apparent volume of distribution and Vss were 5.69 and 4.54 liters/kg, respectively. The mean blood total body clearance was 3.38 ml/min/kg. The literature was reviewed to obtain comparable data from other mammalian species, and satisfactory kinetic information was found for humans, dogs, and rabbits. Interspecies variants in physiological parameters and cyclosporine pharmacokinetics were considered and treated as a property and consequence of body size (allometry), nullifying anatomical and physiological differences between species. A relationship between pharmacokinetic time (a variable in terms of chronological time) and body weight was found. It is suggested that the metabolic capacity (based on liver weight) to eliminate cyclosporine is similar in humans, rabbits, and rats, whereas the dog showed a potentially double capacity to metabolize the drug. However, metabolic and pharmacodynamic studies are also needed to predict toxicity accurately among species.     

The pharmacokinetics of indecainide in mice, rats, dogs, and monkeys

The pharmacokinetics of indecainide, a new antiarrhythmic agent, were studied in mice, rats, dogs, and monkeys. The drug was well absorbed in all species tested resulting in peak plasma levels of drug within 2 hr. The plasma half-life of indecainide after acute oral administration was 3-5 hr in rats, dogs, and monkeys but considerably shorter in mice. The plasma half-life of indecainide was dose-dependent in dogs and increased slightly with chronic dosing. Peak plasma levels of drug were also dose-dependent in dogs and monkeys. Fecal elimination was the primary route of excretion of the drug in rats and mice after oral dosing. Fifty per cent of the dose was excreted in the bile of rats which was then subject to enterohepatic circulation. Urinary elimination was the predominant excretory route in the dog. Tissue distribution of radioactivity in rats showed that tissues which first encounter the drug have the highest levels of radioactivity. The highest concentrations were found in the stomach, intestine, liver, and kidney, whereas very low levels were observed in the fat and brain. Except for liver and kidney, only very low levels were present after 24 hr.