Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Pharmacokinetics of galantamine,a cholinesterase inhibitor,in several animal species

In this publication, single and repeated dose experiments in rats, mice, rabbits and dogs are reported to assess the pharmacokinetics of galantamine (CAS-1953-04-4), a tertiary alkaloid with reversible cholinesterase inhibiting and nicotinic receptor modulatory properties developed for the treatment of Alzheimer's disease in humans. Rats received single i.v. and single and repeated oral administrations of various doses, up to 160 mg/kg/day. In mice, only repeated oral administration of galantamine was investigated, up to 40 mg/kg/day. Galantamine single and repeated oral doses up to 32 mg/kg/day were administered to female pregnant rabbits. Beagle dogs received single i.v. and single and repeated oral administrations of doses up to 8 mg/kg/day. Generally, oral absorption was rapid, with maximal plasma levels reached within 2 h in all species. Absolute oral bioavailability of a gavage dose was high in rat (77%) and dog (78%). In mice and rats, the bioavailability of galantamine administered via the food was lower than of galantamine administered by gavage. Elimination half-life of galantamine was relatively large in rat and dog and smaller in mouse and rabbit. In general, galantamine displayed dose-proportional to somewhat more than dose-proportional kinetics. In rats, plasma levels were lower in females than in males, whereas in mice, females showed higher levels than males. No gender differences were observed in dogs. No relevant differences in exposure to galantamine were found in rats and dogs upon oral administration of galantamine obtained as a natural extract or from chemical synthesis. The exposure to the active metabolite norgalantamine in plasma of the different animal species was low, except in the dog where the steady-state norgalantamine exposure was approximately 75% of galantamine exposure. Galantamine plasma levels after single and repeated administration of 10 mg/kg/day in all species investigated except female rat and rabbit were much higher than mean therapeutic plasma levels of galantamine obtained in humans. The pharmacokinetic profile of galantamine after repeated oral administration in rats was most similar to the profile obtained after repeated administration of 12 mg b.i.d. in man.     

Pharmacokinetics of amosulalol, an alpha, beta-adrenoceptor blocker, in rats, dogs and monkeys

The pharmacokinetics of an alpha, beta-adrenoceptor blocker, amosulalol hydrochloride, were studied after i.v. and oral administration to rats, dogs and monkeys. After an i.v. dose (1 mg/kg), the plasma concentration-time curve fitted a two-compartment open model with terminal half-lives of 2.5 h in rats, 2.1 h in dogs and 1.8 h in monkeys. The order of plasma clearances for amosulalol was: rats greater than dogs greater than monkeys. After oral administration, the maximum plasma concentration was obtained at 0.5-1 h in rats (10-100 mg/kg) and dogs (3-30 mg/kg), and at 1.7-2.7 h in monkeys (3-10 mg/kg). A linear relationship between the area under the plasma concentration-time curve and dose administered was obtained for all three species. The systemic availabilities of the drug in rats, dogs and monkeys were 22-31%, 51-59% and 57-66%, respectively. After repeated oral administration (10 mg/kg) to dogs for 15 days, the pharmacokinetic parameters did not differ significantly from those on the first day.     

Species differences in the pharmacokinetics of recainam, a new anti-arrhythmic drug

The pharmacokinetics of recainam, an anti-arrhythmic drug, were compared in mice, rats, rabbits, dogs, rhesus monkeys, and man. Bioavailability was virtually complete in monkeys and dogs, 67 per cent in man and 51 per cent in rats. Non-linear kinetics between the oral and i.v. dose in rabbits precluded estimation of bioavailability. Linear plasma dose proportionality occurred in dogs between 6 and 60 mg kg-1 oral doses and rhesus monkeys between 1 and 15 mg kg-1 i.v. doses. A greater than proportional increase in the plasma AUC of recainam occurred between oral doses ranging from 54-208 mg kg-1 in mice, 25-110 mg kg-1 in rats, and 50-100 mg kg-1 in rabbits. In human subjects, the AUC/unit dose was linear between 400 and 800 mg. The terminal elimination t1/2 of recainam ranged from 1-5h in laboratory animals and man. The plasma Cmax and AUC of recainam were virtually identical after single or multiple (21 day) oral doses in dogs. After an i.v. dose, plasma clearance of recainam (l kg-1 .h) was 4.9-5.2 in rats and rabbits and 0.4-1.9 in dogs, rhesus monkeys, and man. The steady state volume of distribution was 2-5 times larger than the total body water of laboratory animals and man. Recainam was very poorly bound (10-45 per cent) to the serum proteins of rodents, rabbits, dogs, rhesus monkeys and man. In rhesus monkeys and man, recainam accounted for 10 per cent and 70 per cent, respectively, of the plasma radioactivity at 6 h post-dose. The pharmacokinetic profile of recainam in dogs most closely resembled that of man.     

Pharmacokinetics of FK482, a new orally active cephalosporin, in animals

The pharmacokinetic profile of FK482 was studied in mice, rats, rabbits and dogs after oral dosing and compared with that of cefixime, cefaclor and cephalexin. Considerable differences in oral absorption of FK482 were observed among the animal species. Absolute bioavailabilities of FK482 were 12.6% in mice, 15.3% in rats, 32.3% in rabbits and 72.3% in dogs. In mice and rats, the absorption of FK482 was poor, and was the lowest of the reference antibiotics. FK482 was moderately well absorbed, with higher plasma levels than cefixime in rabbits and, like cefixime, gave higher plasma levels and a longer half-life than cefaclor or cephalexin in dogs. The increase in the area under the serum concentration time curve (AUC) of FK482 was strictly proportional to the increase in dose in the range of 2.5 to 40 mg/kg in rats and dogs, and 2.5 to 20 mg/kg in rabbits and the urinary recovery rates were almost constant. All tissue concentrations of FK482 in rats and rabbits were lower than those of the reference antibiotics and reflected its lower plasma concentrations in these animals. The urinary recovery rates of FK482 were 9.8% for mice, 15.5% for rats, 45.8% for rabbits and 47.1% for dogs. The biliary recovery rate of FK482 was low; 1.4% in rats and less than 0.1% in rabbits and dogs. No active metabolites were detected in the plasma, urine or bile samples from rats, rabbits or dogs. FK482 was mainly absorbed in the jejunum, and was inactivated in the large intestine. The serum-protein binding of FK482 was almost the same as that of cefixime: 60-77% for mouse, rabbit and human serum, and 90-93% for rat and dog serum.     

Pharmacokinetics of YM466, a new factor Xa inhibitor, in rats and dogs.

The pharmacokinetics of YM466, a selective inhibitor for factor Xa, was investigated after single intravenous and oral dosing to rats and dogs. After i.v. dosing, plasma YM466 concentration declined in a bi-phasic manner with a terminal elimination half-life of 1.4 h in rats and 0.8 h in dogs. Total plasma clearance values were 884 and 1212 ml/h/kg in rats and dogs, respectively. After oral dosing, plasma YM466 concentrations reached maximum within 2 h and increased in a dose-proportional manner in rats while increase was nonlinear in dogs. The absolute bioavailability of YM466 was 2.7-4.5% in rats, almost constant regardless of the dose levels investigated, while it was 6.9-24.6% in dogs, indicating nonlinear pharmacokinetics. The plasma protein binding of YM466 was 54.7-56.5% in rats and 45.2-49.0% in dogs and almost constant regardless of the concentration. No metabolism of YM466 was observed in an in vitro liver microsome study. These findings suggest that the low bioavailability of YM466 is attributable to the poor absorption not to the extensive metabolism.     

Pharmacokinetics and tissue distribution of ketanserin in rat, rabbit and dog

The plasma kinetics and tissue distribution of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468) were studied in the rat, rabbit and dog. The studies were performed utilizing 3H- and 14C-labelled ketanserin and appropriate techniques to measure levels of radioactivity, unchanged drug and a major metabolite ketanserin-ol in plasma and tissues. Following intravenous administration to male rats and dogs (10 mg/kg), plasma levels could be described by a two-compartment model. The plasma clearance (C1) averaged 3.8 and 19.2 ml/min/kg and the volume of distribution (Vdss) 0.67 and 4.7 l/kg in male rats and in dogs, respectively. Following oral administration (10-40 mg/kg), ketanserin was rapidly and completely absorbed in all species studied. The absolute bioavailability of oral ketanserin was more than 80% in both rats and dogs. Due to the high clearance of the metabolites in rats, ketanserin was the main component of the plasma radioactivity. In dogs, the fraction of the metabolite ketanserin-ol was more pronounced than that of ketanserin. The apparent elimination half-life of ketanserin was 1.5 h in rabbits, 2-5 h in rats and 3-15 in dogs. The pharmacokinetics of ketanserin were dose-related after single and chronic intravenous and oral dosing. Distribution studies in rats after intravenous and oral administration (10 mg/kg) demonstrated an almost immediate equilibrium between plasma and tissues, resulting in slightly higher tissue than plasma concentrations in the well perfused tissues, and similar or slightly lower levels in the remaining tissues. Ketanserin was the main component of tissue radioactivity. The drug crossed the blood-brain barrier only to a slight extent, brain levels of the unchanged drug being similar to the free fraction in plasma. Ketanserin disappeared from tissues with a similar half-life to that in plasma. On repeated dosing, a small fraction of metabolites was more slowly eliminated. The excretion of the urinary and faecal metabolites after repeated dosing was very similar to that after a single dose. Placental transfer of ketanserin in the rat was limited. On average 0.3% of the maternal radioactive dose, preferentially metabolites, was recovered from the combined foetuses. In dogs orally treated with doses of up to 40 mg/kg/d for 12 months, no undue accumulation or retention of ketanserin or ketanserin-ol was found in any tissue. In lactating dogs orally dosed at 10 mg/kg, preferentially metabolites were excreted in the milk. Concentrations of ketanserin and ketanserin-ol in the milk were respectively 2 and 4 times higher than plasma levels.     

A correlation between the species differences in anti-inflammatory activity of AD-1590, a non-steroidal anti-inflammatory drug, and its plasma level

Authors have reported that the oral potency ratio of AD-1590 to indomethacin varies with the animal models employed; the ratio is 4, 2.3 and 31 in the tests of acetic acid-induced vascular permeability (male mice), carrageenan hind paw edema (male rats) and UV-erythema (female guinea pigs), respectively. Thus, the relationship between the difference in the anti-inflammatory activity of AD-1590 among animal models and the species difference of the plasma AD-1590 level was investigated in experimental animals in order to ascertain the cause of the difference in the potency ratio. Inhibitory potency of AD-1590 on UV-erythema and increased vascular permeability induced by acetic acid in male rats was about 2.1 and 2.3 times, respectively, that of indomethacin. On the other hand, after a single oral administration of 5 mg/kg, the highest plasma AD-1590 level was seen in female guinea pigs (AUC9-8 hr = 63.1 micrograms.hr/ml); and followed by that in mice (male, 32.1; female, 36.1) greater than male dogs (11.5) greater than or equal to rats (male, 9.02; female, 12.5), male rabbits (9.17) greater than male monkeys (9.34 at 6 mg/kg). Hucker et al. have reported that the plasma level of indomethacin in rats is several times higher than that in guinea pigs, rabbits and monkeys. These results suggest that most of the species difference in the relative potency of AD-1590 to indomethacin in the anti-inflammatory activity results from the species difference in the plasma level of both drugs.     

Pharmacokinetics of YK754, a novel If channel inhibitor in rats, dogs and humans

The pharmacokinetics of YM758, a novel funny If current channel (If channel) inhibitor, was investigated after single intravenous (i.v.) and oral dosing to rats and dogs, and partially compared with the results in humans by using liver microsomes. After i.v. administration, the plasma YM758 concentrations decreased, with an elimination half-life (t(1/2)) of 1.14-1.16 h in rats and 1.10-1.30 h in dogs. Total body clearance (CL(tot)) was 5.71-7.27 and 1.75-1.90 L/h/kg in rats and dogs, respectively which was comparable to the hepatic blood flow rate. In dogs, the pharmacokinetic profiles for i.v. bolus administration and continuous infusion did not differ. After oral administration, the levels of YM758 in rat plasma increased more than dose-proportionally, whereas almost linear pharmacokinetics were observed in dogs. Absolute bioavailability was 7.5%-16.6% in rats and 16.1%-22.0% in dogs. The plasma protein binding saturation of YM758 was observed in dogs and humans; this finding is consistent with the result that the major binding protein of YM758 in plasma is alpha1-acid glycoprotein (AGP), in particular in humans. The blood-to-plasma partition coefficient values were 1.36-1.42 in rats, 0.95-1.15 in dogs and 0.71-0.85 in humans. The results of the metabolic study on liver microsomes indicated that the non-linear pharmacokinetics of YM758 observed in rats may be partially due to a first-pass effect in the gastrointestinal tract and the liver.     

Pharmacokinetic properties of TDP4815 after single intravenous and oral administrations to rat, rabbit, monkey, dog and in vitro drug metabolism

The pharmacokinetics of TDP4815 was evaluated in rats, rabbits, dogs and monkeys. After intravenous administration, TDP4815 achieved C(O) of 3255 ng/ml in rats at 5 mg/kg, 9066 ng/ml in rabbits and 7858 ng/ml in monkeys at 6 mg/kg, and 4457 ng/ml in dogs at 3 mg/kg. The clearance (C(L)) was 3105, 1692, 835 and 640 ml/h/kg in rats, rabbits, monkeys and dogs, respectively. The volume of distribution (V(Z)) was more than 3861 ml/kg in all species, except 1915 ml/kg in monkeys. The oral bioavailability was rabbit >rat> monkey compared at 100 mg/kg, but it was much higher in dogs (>64%) after oral administrations. The calculated intrinsic clearance data suggested that the clearance of dog and human was restricted by binding to the plasma protein, and the clearance of rat and monkey was dependent on both the free fraction of plasma protein binding and the liver blood flow rate. The unbound hepatic intrinsic clearance of monkey was close to its C(L) suggesting that the hepatic clearance was an important excretion in monkeys. The poor oral bioavailability in the monkey may be related to the extensive glucuronidation. The V(Z).kg and C(L).kg in test species showed good correlation with the animal body weights (R(2)=0.87 and 0.96).     

Pharmacokinetics of nimodipine. I. Communication: absorption, concentration in plasma and excretion after single administration of [14C]nimodipine in rat, dog and monkey

Studies on absorption, plasma concentrations and excretion with (+/-)isopropyl-2-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nimodipine, Bay e 9736, Nimotop) have been conducted in rat, dog and monkey using the carbon-14-labelled substance and a wide range of doses (0.05-10 mg/kg) administered via different routes (intravenous, oral, intraduodenal). Nimodipine was well absorbed in all species. Peak plasma concentrations of radioactivity were determined 28-40 min (male rat), 60 min (female rat), about 3 h (dog) and 7 h (monkey) after administration. Dependent on the observation period (24-216 h) terminal half-lives for the elimination of radioactivity from plasma ranging between 4.6 h (female rat) and 157 h (dog) were observed. Comparing the AUC, the concentration of unchanged [14C]nimodipine in plasma represented only a small (maximally 37% in dogs after i.v. dose) to negligible (about 1%, monkey after oral dosing) part of the total radioactivity. Excretion of radioactivity via feces and urine was rapid in all species after both oral and intravenous dosing. Fecal (biliary) excretion was the major excretory route in rat and dog. The monkeys excreted about 40 to 50% via the urine. Residues in the body never exceeded 1.5% of the dose. [14C]nimodipine and/or its radiolabelled metabolites were secreted in milk of orally dosed lactating rats. Binding of [14C]nimodipine to plasma proteins of rat and dog was about 97%.     

The pharmacokinetics of Casodex in laboratory animals.

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs. 2. The binding of 14C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values greater than 95%; in dog there was evidence for decreased binding at concentrations greater than 12 micrograms/ml. 3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1 mg/kg to 10% and 12% at 250 mg/kg; in dog bioavailability decreased from 100% at 0.1 mg/kg to 31% at 100 mg/kg. 4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10 mg/kg but not at 250 mg/kg; in dog appreciable accumulation (9-12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10 mg/kg, but at 100 mg/kg the accumulation ratio was much lower (4-fold).     

The pharmacokinetics of Casodex in laboratory animals

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs.

2. The binding of ¹⁴C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values >95%; in dog there was evidence for decreased binding at concentrations >12 μg/ml.

3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1?mg/kg to 10% and 12% at 250?mg/kg; in dog bioavailability decreased from 100% at 0.1?mg/kg to 31% at 100?mg/kg.

4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10?mg/kg but not at 250?mg/kg; in dog appreciable accumulation (9–12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10?mg/kg, but at 100?mg/kg the accumulation ratio was much lower (4-fold).     

Assessment of oral bioavailability and preclinical pharmacokinetics of DRF-6196, a novel oxazolidinone analogue, in comparison to linezolid.

The aim of this study was to determine the bioavailability of a novel oxazolidinone, DRF-6196, in mice and rats following intravenous (i.v) and oral dosing and to compare the pharmacokinetics with those obtained following linezolid dosing. Blood samples were drawn at predetermined intervals up to 24 h post-dose after either DRF-6196 or linezolid administration. The concentrations of DRF-6196 and linezolid in various plasma samples were determined by a HPLC method. Following oral administration maximum concentrations of DRF-6196 were achieved within 0.5 h irrespective of the species. While the doses increased in the ratio of 1 : 3 : 10, mean Cmax and AUC(0-infinity) values in mice for DRF-6196 increased in the ratio of 1 : 3.87 : 8.53 and 1 : 2.51 : 9.24, respectively. Both the Cmax and AUC(0-infinity) values increased almost proportional to the dose administered in mice. Following i.v administration, the concentration of DRF-6196 declined in a bi-exponential fashion with terminal elimination half-life of 1.5 h irrespective of the species. The systemic clearance and volume of distribution of DRF-6196 in mice were 1.14 L/h/kg and 0.66 L/kg, respectively after i.v administration, while the respective values in rats were 0.61 L/h/kg and 0.41L/kg, respectively. Elimination half-life ranged between 0.8-1.5 h. Absolute oral bioavailability of DRF-6196 was found to be 80-96% across the test dose range. Although plasma levels of DRF-6196 were lesser compared to linezolid in the initial hours, it may not have any consequences on the clinical effectiveness of the molecule.     

Pharmacokinetics of E-6087, a new anti-inflammatory agent, in rats and dogs.

The pharmacokinetics of E-6087, a newly developed cyclooxygenase-2 inhibitor, was studied in rats and dogs after single oral and intravenous doses. In both animal species, E-6087 was characterized by a long elimination half-life (20-35 h), a low plasma clearance (0.10-0.22 l h(-1) kg(-1)) and a relatively large volume of distribution (2-6 l kg(-1)). Oral bioavailability was lower in dogs than in rats whereas a faster elimination was found in rats. Multiple peaks were present regardless of administration route and animal species, suggesting the existence of enterohepatic circulation. Gender effect on the pharmacokinetics of E-6087 was only found in rats, with greater exposure and longer elimination in females than in males. Food intake reduced the bioavailability (approximately 22%) with no apparent changes in the absorption rate. After oral dosing of 1, 5 and 25 mg kg(-1) to rats, linearity was lost at the highest dose due to the low aqueous solubility of E-6087. Drug absorption was improved by micronization. E-6087 and E-6132, (a pharmacologically active metabolite), showed different pharmacokinetics. The higher percentage of E-6087 at early times suggests that E-6087 is the main compound responsible for in vivo activity, although E-6132 would contribute to the activity at later times.     

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Absorption,distribution and excretion of lacidipine,a dihydropyridine calcium antagonist,in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog).

2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism.

3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug.

4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species.

5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses.

6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration.

7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog

The plasma kinetics and tissue distribution of the gastrokinetic (+/-)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4- piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration to rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min.kg and 4.7 l/kg in the rat and 4.2 ml/min.kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of monobutylphthalate, the active metabolite of di-n-butylphthalate, in pregnant rats

Di-n-butylphthalate (DBP) is a phthalic acid ester used as a plasticizer and solvent. DBP is a developmental toxicant in rats and mice, with adverse effects arising from the monoester metabolite monobutyl phthalate (MBP). The objective of this study was to evaluate the pharmacokinetics of MBP and monobutyl phthalate glucuronide (MBP-G) in pregnant rats following intravenous (i.v.) dosing with MBP. Pregnant dams were i.v. dosed with aqueous MBP (10, 30, or 50mg MBP/kg body weight) on gestation day (GD) 19. The pharmacokinetics of MBP and MBP-G were rapid: MBP was metabolized to MBP-G within 5 min, and MBP and MBP-G disappeared from maternal and fetal plasma within 24h of dosing. Results were consistent with two previous studies that utilized oral doses of DBP, suggesting that chemical (DBP versus MBP), vehicle (oil versus aqueous), dose level, and route (oral versus i.v.) have minimal effects on the maternal pharmacokinetics of MBP and MBP-G. This study provides direct pharmacokinetic analysis for MBP and MBP-G in pregnant rats during fetal male reproductive development, and indicates that future pharmacokinetic or toxicology studies can reliably utilize oral dosing with DBP.     

Pharmacokinetics of besulpamide in rats and dogs

The pharmacokinetics of besulpamide were studied in rats and its urinary excretion in rats and dogs. Kinetic characteristics were the same for both male and female rats according to a two-compartment open model. Biological half-life was 1-4 hr, absorption half-life was approximately 10 min and absolute bioavailability was nearly complete (F = 86.4%). In rats, urinary excretion of unchanged besulpamide was 30% after i.v. administration and 7% after oral administration, whereas in dogs after oral administration it was 54%. Values of the area under the plasma concentration-time curve in rats and percent of urinary excretion in dogs show that the kinetics of besulpamide are not dose-related when the drug is administered at doses of 10-50 mg/kg.