Disposition of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl) dopamine (TA-870) in humans

Dopamine (DA) levels in human plasma after oral administration of TA-870 and iv infusion of DA were measured by HPLC. The metabolites of TA-870 or DA in plasma and urine were also determined. The maximal concentrations (Cmax) of free DA in plasma after oral administration of 750 and 1500 mg of TA-870 to humans were 63 and 127 ng/ml, respectively, being higher than the concentrations of 8 and 31 ng/ml following the infusion of 1 and 3 micrograms/kg/min, the clinical doses of DA. These results demonstrated the clinical usefulness of TA-870. The plasma level of free deethoxycarbonylated TA-870 (DEC-TA-870) after oral administration of TA-870 was higher than that of DA. After oral administration of TA-870, the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma was higher than that after DA infusion, but the concentration of homovanillic acid (HVA) was about the same as that after DA infusion. The level of the total urinary metabolites (free and conjugated) after oral administration of TA-870 decreased as follows: DA greater than HVA greater than DOPAC greater than DEC-TA-870. The conjugated/free ratios of urinary metabolites after TA-870 dosing were 40-66 for DA, 0.5 for HVA, 0.6-0.9 for DOPAC, and 5.0-6.2 for DEC-TA-870. The composition of urinary metabolites after oral dosing of TA-870 was almost the same as that the DA metabolites. These results show that TA-870 is rapidly converted to DA in the human body.     

A novel, orally active dopamine prodrug TA-870. V. Natriuretic and positive inotropic effects in rats: an assessment after chronic administration.

We investigated the acute natriuretic and positive inotropic effects of the dopamine prodrug TA-870 in rats before and after repeated administration for 2 weeks. Single intraduodenal (i.d.) administration of TA-870 (10-250 mg/kg) to saline-loaded anesthetized rats produced a dose-dependent increase in urinary flow and sodium excretion. It also produced a decrease in renal vascular resistance and an increase in renal blood flow. In another series of normal anesthetized rats, TA-870 caused dose-dependent increases in cardiac contractility [left ventricular dP/dtmax (LV dP/dtmax)] at i.d. doses of 10-250 mg/kg. Although the heart rate was also increased, this effect was much smaller than the effect on LV dP/dtmax. SCH-23390 (0.3 mg/kg i.v.), a selective DA1 dopamine receptor antagonist, strongly inhibited the above diuretic, natriuretic, and renal vasodilatory effects of TA-870. The positive inotropic effect of TA-870 was not inhibited by SCH-23390, but the latter effect was inhibited by pretreatment with propranolol (0.5 mg/kg i.v.). After repeated oral administration of TA-870 to rats (250 mg/kg twice a day for greater than 2 weeks), there was no significant differences in the natriuretic and positive inotropic responses to TA-870 between the TA-870-pretreated and control groups indicating a lack of pharmacological tolerance. In conclusion, TA-870, when administered enterally to rats, produced the natriuretic effect via the DA1 dopamine receptor and positive inotropic effects via the beta 1 adrenergic receptor stimulation, and these effects were not attenuated by chronic treatment with TA-870.     

Metabolic fate of the new Ca++-channel blocking agent (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate. Distribution, excretion and protein binding in rats and dogs

Distribution, excretion and protein binding of (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate (TA-3090) in rats and dogs were investigated after oral (30 mg/kg (rats), 2 mg/kg(dogs] and intravenous (3 mg/kg (rats), 0.2 mg/kg (dogs) administration of 14C-TA-3090. Plasma level of radioactivity in rats reached plateau (6.04 micrograms equiv. of TA-3090 free base/ml) 1 h after oral administration. The plateau level continued at least up to 6 h. The plasma concentration of the unchanged drug (free base) reached the maximum (425 ng/ml) at 45 min after oral administration, and then decreased with a half-life of 1.16 h. Plasma level of radioactivity after intravenous administration to rats rose gradually up to 1 h and thereafter it was kept constant for 6 h. Plasma concentration of the unchanged drug decreased with half-lives of 0.43 h (alpha phase) and 1.33 h (beta phase) after intravenous administration. In dogs, the peak level of plasma radioactivity after oral administration was 227 ng/ml at 1 h. The Cmax, Tmax and t1/2 of unchanged drug were 31 ng/ml, 1.34 h and 4.13 h, respectively. The plasma levels of total radioactivity and unchanged drug after intravenous administration to dogs were 146 and 142 ng/ml at 1 min, respectively. The t1/2 of the plasma radioactivity were 0.02 h (alpha) and 4.02 h (beta). Those of unchanged drug were 0.03 h (alpha) and 1.66 h (beta).(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel orally active dopamine prodrug TA-870. I. Renal and cardiovascular effects and plasma levels of free dopamine in dogs and rats

Intraduodenal administration of N-(N-acetyl-L-methionyl)-O, O-bis(ethoxycarbonyl)dopamine (TA-870), a newly synthesized dopamine derivative, increased the renal blood flow (RBF) and mesenteric blood flow in anesthetized dogs, while blood pressure and heart rate were less affected. It also increased the glomerular filtration rate, urine volume, and urinary sodium excretion in saline-loaded anesthetized dogs. In conscious dogs, TA-870 and dopamine hydrochloride (DA-HCl) increased RBF in parallel with increases in plasma free dopamine (free-DA) concentration. At an equimolar dose of 71 mumols/kg, p.o., the effect of TA-870 continued for greater than 4 h, while that of DA-HCl lasted for only 2 h: the peak free-DA concentration and maximum increase in RBF were 155 +/- 57 ng/ml and 56 +/- 15%, respectively, for TA-870, and those for DA-HCl were 32 +/- 13 ng/ml and 36 +/- 10%. Similarly, TA-870 showed greater increases in both RBF and plasma free-DA concentration than DA-HCl in anesthetized rats. In contrast to enteral administration, intravenously administered TA-870 exhibited weaker effects than intravenous DA-HCl in anesthetized dogs. In conclusion, TA-870 is an orally effective dopamine prodrug capable of producing higher and more sustained plasma concentrations of dopamine than DA-HCl when administered by the enteral route.     

Observations on the absorption, distribution, metabolism, and excretion of the dopamine (D2) agonist, quinelorane, in rats, mice, dogs, and monkeys.

Following the oral administration of [14C]quinelorane, a potent and highly specific dopamine (D2) agonist, to rats, mice, and monkeys, the compound was well absorbed, with 50% or more of the radioactivity appearing in the urine within 24 hr. Dogs were pretreated with 22 consecutive daily doses of quinelorane by the oral route (in order to induce tachyphylaxis to the emetic effect) before receiving an iv dose of [14C]quinelorane; just over 80% of the radioactivity was excreted into the urine. A tissue-distribution study in rats receiving a single oral dose of 0.1 mg/kg [14C]quinelorane indicated a widespread distribution of radioactivity, with levels being notably low in the blood and plasma and high in the salivary gland, adrenals, pancreas, and spleen; levels were highest in the stomach and kidneys. The Tmax of radiocarbon in the 22 tissues varied between 0.5 and 6 hr, with some tissues showing a plateau of radioactivity between these time-points. After 8 hr, levels of radioactivity were clearly decreasing, and by 48 hr, background levels were attained. Following the oral and iv administration of quinelorane to rats, the systemic bioavailability was calculated to be 16% and the volume of distribution was found to approximate that of total extracellular water, i.e. approximately 300 ml/kg. Since absorption was satisfactory and the tissue distribution study indicated widespread radioactivity, the low bioavailability may be due to first-pass metabolism. Rats excreted marginally more of the N-despropyl metabolite than unchanged drug into the urine, and dogs excreted principally unchanged quinelorane into their urine, followed by the N-despropyl metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)     

First pass metabolism and in vitro metabolism of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine in dogs.

To elucidate the first pass metabolism of the dopamine prodrug N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) in the small intestine and liver of dogs, the blood and plasma concentrations of unchanged TA-870 and metabolites in the gastroduodenal vein, portal vein, hepatic vein, and abdominal aorta were measured by HPLC after intraduodenal administration of TA-870. In addition, an in vitro metabolic study of TA-870 was carried out using liver, small intestinal wall, and blood homogenates of dogs. The order of maximal concentration (Cmax 0-30 min) in gastroduodenal blood or plasma was unchanged TA-870 greater than deethoxycarbonylated TA-870 (DEC-TA-870) greater than conjugated dopamine greater than free dopamine (DA) greater than free homovanillic acid (HVA) greater than free 3,4-dihydroxyphenylacetic acid (DOPAC). This result showed that the main pathway of metabolism in the small intestine is catechol ester hydrolysis and minor pathways are amido hydrolysis, oxidative deamination, and catechol 3-O-methylation. The order of Cmax in the hepatic vein and abdominal aorta was conjugated DA greater than free DEC-TA-870 greater than free HVA greater than free DA greater than free DOPAC greater than conjugated DOPAC greater than unchanged TA-870. The main metabolic pathways in the liver were hydrolyses of ester and amido-linkage of TA-870 and conjugation of DA. In the in vitro studies, the main metabolites of TA-870 in liver, small intestinal wall, and blood homogenates were DEC-TA-870, 3- or 4-mono-deethoxycarbonylated TA-870, DA, and an unknown compound.(ABSTRACT TRUNCATED AT 250 WORDS)     

The biotransformation of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. After oral or intravenous doses (0.25?mg/kg) of [¹⁴C]lormetazepam to rats, most of the urinary radioactivity was associated with polar components and < 1% dose was excreted as unconjugated lormetazepam. About 30% of an oral dose was excreted in rat bile as a conjugate of lormetazepam and about 50% dose as polar metabolites. Plasma also contained mainly polar metabolites, and unchanged lormetazepam represented at most 10% of total plasma radioactivity after an oral dose.

2. Almost all the radioactivity in dog, rhesus monkey and rabbit urine, after oral or intravenous doses (0.5–0.7?mg/kg) of [¹⁴C]lormetazepam, was associated with conjugated material. In the dog there were only two major components, conjugates of lormetazepam and lorazepam (N-desmethyl-lormetazepam) which accounted for about 24% and 14% respectively of the oral dose in the 0–24?h urine. The same two conjugated components were also present in dog bile. Conjugated lormetazepam was the only major component in monkey and rabbit urine and accounted for about 60% dose in the 0–24?h urine of each species, while conjugated lorazepam accounted for only about 0.5% and 4% respectively.

3. Dog and monkey plasma contained mostly conjugated material after oral and intravenous doses (0.05–0.07?mg/kg of [¹⁴C]lormetazepam. Dog plasma after an oral dose contained conjugates of both lormetazepam and lorazepam with peak concn. at 1?h of 130 and 47 ng/ml respectively. Concn. of these conjugates in plasma declined with apparent terminal half-lives of about 17 and 27?h respectively after oral doses, and 13?h in both cases after intravenous doses. Conjugated lormetazepam was the only major component in monkey plasma representing a peak concn. of 180 ng/ml at 1?h after an oral dose, and declined with an apparent terminal half-life of about 11?h after oral or intravenous doses.

4. Lormetazepam crosses the placental ‘barrier’ of rabbits: its concn. in the foetus were similar to those in maternal plasma after intravenous doses.     

A novel orally active dopamine prodrug TA-870. II. Evidence that TA-870 is a dopamine prodrug

The mechanism of action of a new orally active dopamine (DA) prodrug, TA-870 (N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)(DA) was studied. When TA-870 (1 mg/kg) was injected in anesthetized dogs, renal vascular resistance was decreased and renal blood flow was increased. The renal vasodilatory effect of TA-870 correlated with the plasma level of DA but not with the level of de-ethoxycarbonyl metabolite of TA-870 (i.e., N-(N-acetyl-L-methionyl)DA; DEC-TA-870). The renal vasodilatory effect of TA-870 was inhibited strongly by haloperidol and slightly by propranolol. Pretreatment with phenoxybenzamine enhanced the renal vasodilatory effect of TA-870. In the isolated rabbit splenic artery, TA-870 and DEC-TA-870 showed no effects, whereas dopamine showed a contracting effect, which was inhibited by phentolamine. In the propranolol- and phentolamine-treated splenic artery, TA-870 and DEC-TA-870 caused weak relaxant effects on PGF2 alpha-induced contraction. These effects were not antagonized by metoclopramide. On the other hand, DA showed a strong relaxant effect, which was competitively inhibited by metoclopramide. In addition, TA-870 and DEC-TA-870 further relaxed the artery that had been maximally relaxed by DA. We concluded that TA-870 and DEC-TA-870 exert weak vasodilatory effects that are different from that of DA in vitro, and that TA-870 exerts its vasodilatory effect after its conversion to free DA in vivo.     

The metabolic fate of Sormodren (bornaprine hydrochloride) in animals and humans

1. Single oral doses of the anticholinergic drug [¹⁴C]Sormodren to rats (1?mg/kg), dogs (0.3?mg/kg) and humans (0.03?mg/kg) were well absorbed. Excreted in urine and faeces were means of 31 and 70%, 53 and 39%, and 78 and 4% in rats, dogs, and humans, respectively, during five days: excretion was prolonged and still incomplete at five days in humans.

2. Peak plasma levels of ¹⁴C (scaled for dose) were generally reached within 1–2h after oral doses in rats, 49 (ng/ml)/(mg/kg), dogs 290 (ng/ml)/(mg/kg) and humans 410(ng/ml)/(mg/kg), and declined with half-lives of approx. 5, 12 and 30?h, in these species respectively. Repeated oral doses of [¹⁴C]Sormodren to dogs resulted in some accumulation of ¹⁴C in the plasma.

3. Tissue concn. of ¹⁴C in dogs were generally higher than those in rats, particularly in the brain, lungs and eyes. The tissue distribution of ¹⁴C in rats and dogs was consistent with that of a compound readily eliminated by both renal and hepatic routes.

4. Basic metabolites in dog and human, urine and plasma were investigated using a combination of?h.p.l.c. and g.l.c.-mass spectrometry. Unchanged Sormodren was not detected in the dog samples and was only a minor component in human urine and plasma. Some metabolites were present as conjugates.

5. A basic extract of enzyme-hydrolysed dog urine (5?mg/kg dose) contained 42% of the urine ¹⁴C. The major metabolites in this fraction were identified as three isomers of monohydroxy-N-desethyl-Sormodren and three isomers of monohydroxy-Sormodren, resulting from hydroxylation in the bicyclic ring. The positions of oxidation were not determined. A similar extract from dog urine (0.3?mg/kg dose) contained 26% of the urine ¹⁴C and the major metabolites were identified as isomers of monohydroxy-N-desethyl-Sormodren.

6. A basic extract of enzyme-hydrolysed human urine (0.03?mg/kg dose) contained 23% of the urine ¹⁴C. The unchanged drug was only a minor component and most of the radioactivity was associated with five isomers of monohydroxy-Sormodren, hydroxylation having occurred in the bicyclic ring.

7. Basic extracts of dog and human plasma only contained about 10% of the plasma ¹⁴C. Metabolites were chromatographically similar to the hydroxylated metabolites identified in the corresponding urine samples.     

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 nisoldipine. I. Absorption, concentration in plasma, and excretion after single administration of [14C]nisoldipine in rats, dogs, monkey, and swine

The absorption, disposition and excretion of (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) have been studied following a single administration of the 14C-labelled compound to rats, dogs, monkey and swine via different routes (intravenous, oral, intraduodenal) in the dose range of 0.05-10 mg.kg-1. [14C]nisoldipine was absorbed rapidly and almost completely. Peak concentrations of radioactivity in plasma were reached 0.9 h (rat), 1.4 h (dog), and 3.6 h (monkey) after oral administration with normalized maximum concentrations being in the same range for all three species (0.49-0.79). The radioactivity was eliminated from plasma with half-lives between 42 h and 54 h within an observation period up to 3 days. The contribution of unchanged [14C]nisoldipine to the concentration of total radioactivity in plasma was low after oral administration (between 0.5% (monkey) and 3.4% (dog) in the peak) indicating an extensive presystemic elimination of this compound. The bioavailability was estimated at 3.4% in rats and 11.7% in dogs. [14C]nisoldipine was highly bound to plasma proteins with free fractions of 0.9-2.9%. The excretion of the radioactivity via urine and feces/bile both after oral and intravenous administration of [14C]nisoldipine occurred rapidly and almost completely within 48 h in all species. Very small residues in the body were recovered at the end of the experiments in rats and dogs (less than 1.6% of the dose). The biliary/fecal route of excretion was preferred in rats, dogs and swine, whereas in monkey 76% of the dose was excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological study of TA-0910, a new thyrotropin-releasing hormone (TRH) analog (II): Involvement of the DA system in the locomotor stimulating action of TA-0910

The mechanism of the locomotor stimulating action of a new thyrotropin-releasing hormone (TRH) analog, TA-0910, was studied in rats. The locomotor stimulating action of TA-0910 (3 mg/kg) was inhibited by haloperidol or alpha-methyl-p-tyrosine (alpha-MT); slightly inhibited by phenoxybenzamine, prazosin, clonidine, or naloxone; not affected by propranolol, metergoline, or a low dose of scopolamine; and was enhanced by a high dose of scopolamine. The locomotor activity was increased by TA-0910 (0.3 mg/kg) in combination with methamphetamine, apomorphine, or L-DOPA under pretreatment with pargyline. A low dose of apomorphine inhibited the increase in locomotor activity induced by TA-0910 (3 mg/kg). The increase in locomotion was most notable and dose-dependent with the injection of 20 ng or more in the nucleus accumbens. The intravenous administration of TA-0910 produced dose-dependent and significant hyperlocomotion at 1 mg/kg or more. In the rats lesioned unilaterally in the nigrostriatal dopamine (DA) pathway by 6-hydroxydopamine, TA-0910 induced ipsilateral circling behavior at 3 mg/kg or more. This circling behavior was inhibited by haloperidol or alpha-MT. These results suggest that the locomotor stimulating action of TA-0910 is mediated primarily via the dopaminergic neuron, especially the nucleus accumbens of the mesolimbic DA system. Other possible mechanisms are also discussed.     

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.     

The pharmacokinetics of nitrendipine. I. Absorption, plasma concentrations, and excretion after single administration of [14C]nitrendipine to rats and dogs

[14C]nitrendipine (3-ethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, Bay e 5009, Baypress, Bayotensin) was administered to rats and dogs (intravenously, orally, intraduodenally, 0.5-50 mg/kg) in order to investigate absorption, disposition, and excretion of parent compound and metabolites. The absorption of radioactivity following oral administration of [14C]nitrendipine was rapid and almost complete in both species. Maximum concentrations of total radioactivity in plasma were reached after 1.2 (rat) or 0.7 h (dog). The radioactivity was eliminated from plasma with terminal half-lives of 57 (rat) and 188 h (dog) during an observation period up to 10 and 9 days, respectively. Unchanged nitrendipine contributed to the AUC of total radioactivity only 8-9% after intravenous and 1-2% after oral administration. The bioavailability of nitrendipine after oral administration amounted to 12% in rats and 29% in dogs due to a strong first pass elimination process. About two thirds of the radioactivity administered were excreted via faeces, one third via urine. Distinct sex-differences in the excretion pattern could be found in rats but not in mice. They were attributed to well-known sex differences of the metabolic capacities in rat liver. In rats the radioactivity excreted via bile (about 75% of the dose) was subject to a marked entero-hepatic circulation, about 50% of the amount excreted being reabsorbed. The radioactive residues in the body were low (0.5% of the dose after 2 days in rats; less than or equal to 0.6% after 9 days in dogs).     

Cardiorenal effects of an orally active dopamine prodrug (TA-870) in patients with congestive heart failure

The effects of TA-870, a newly synthesized orally active dopamine prodrug, on the cardiorenal functions were investigated in 12 patients with severe chronic congestive heart failure. A single oral dose of TA-870 (1,200 mg) improved left ventricular fractional shortening and mean circumferential velocity on M-mode echocardiography (p less than 0.01 for both). Renal plasma flow and glomerular filtration rate improved with TA-870 (p less than 0.01 and p less than 0.05, respectively); urine volume and sodium excretion increased (p less than 0.01 for both). Blood pressure and heart rate did not change during the 4-h experimental period. Mean plasma free dopamine levels peaked 1 h after dosing. These data suggest that the cardiorenal effects of oral TA-870 are comparable with those of continuous intravenous injections of dopamine. Thus, TA-870 appears to be a useful alternative drug to intravenous dopamine.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 1st communication: absorption, pharmacokinetics and excretion in rats and dogs.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) is an ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, 6366 A (CAS 89371-44-8). Absorption, pharmacokinetics and excretion of imidapril were studied in rats and dogs after oral and intravenous administration of [N-methyl-14C]-imidapril and [N-methyl-14C]-6366 A (1 mg/kg). Following oral administration of 14C-labeled imidapril and 6366 A to rats, plasma concentrations of radioactivity were much higher after [N-methyl-14C]-imidapril dosing than after [N-methyl-14C]-6366 A dosing at all time points. Imidapril was relatively rapidly absorbed from the digestive tract and easily metabolized to the pharmacologically active 6366 A after oral dosing in the rats and dogs. Thus, imidapril proved to be an orally usable 6366 A prodrug. More than 62% and 38% of the dose were assumed to be absorbed from the gastrointestinal tract in the rats and dogs, respectively. The in situ absorption study showed that [N-methyl-14C]-imidapril was absorbed from nearly the entire rat small intestine, especially from the jejunum, but hardly absorbed from the stomach. After oral administration, peak levels of radioactivity in the plasma occurred at 1 h in rats and 30 min to 2 h in dogs. The disappearance of unchanged drug from the plasma was much faster in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

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 absorption, tissue distribution and excretion of di-n-octyltin dichloride in rats

In this study the absorption, tissue distribution and excretion of 14C-labeled di-n-octyltin dichloride ([14C]DOTC) in rats were investigated after oral and intravenous (i.v.) administration. Although after i.v. administration with 1.2 mg [14C]DOTC/kg body weight the tissue radioactivity was about 3-4 times higher than after oral administration with 6.3 mg [14C]DOTC/kg body weight, the relative tissue accumulation was found to be the same after the oral and i.v. dosage. The highest amount of radioactivity was found in liver and kidney, and to a lesser degree in adrenal, pituitary and thyroid glands. The lowest activity was recovered from blood and brain. No selective accumulation was observed in thymus, although it has been reported that thymus atrophy is the most sensitive parameter of DOTC toxicity in rats. For all tissues a time dependent decrease in radioactivity was found, except for kidney. The excretion of radioactivity in feces and urine was determined after a single i.v. or oral dose of 1.2 and 2 mg [14C]DOTC, respectively. After i.v. administration most of the radioactivity was excreted in the feces which was characterized by a biphasic excretion pattern. In orally treated rats more than 80% of the radioactivity was already excreted in the feces during the first day after administration. This indicated that only a small part of the DOTC was absorbed, which was calculated to be approximately 20% of the dose. Similar half-life values of 8.3 and 8.9 days were obtained from the fecal excretion of radioactivity after the i.v. and oral administration, respectively. The urinary excretion of radioactivity appeared to be independent of the body burden, since the daily amount of radioactivity excreted in urine was nearly the same independent of the route of administration as well as the time after administration.     

A novel orally active dopamine prodrug TA-870. III. Positive inotropic effect and cardiorenal selectivity in anesthetized dogs.

The effect of TA-870, a novel dopamine prodrug, on the cardiovascular system was studied in anesthetized open- and closed-chest dogs. Intraduodenal administration of less than or equal to 12 mg/kg TA-870 to anesthetized dogs increased left ventricular (LV) dP/dtmax and dP/dt/Pmax. Furthermore, at a lower dose of TA-870 (2 mg/kg), renal vascular resistance (RVR) decreased and renal blood flow (RBF) increased. Similarly, total peripheral resistance (TPR) decreased and cardiac output (CO) increased at less than 4 mg/kg. In an intravenous cumulative dose-response study of TA-870, the plasma-free-dopamine concentration was elevated depending on the dose of TA-870. Renal vasodilation occurred at a low plasma-free-dopamine concentration, whereas a positive inotropic action required higher plasma-free-dopamine. However, the dose-response curve for LVdP/dt/Pmax was steeper than that for RBF or CO. Heart rate was less affected than LVdP/dt/Pmax in open-chest dogs and decreased in closed-chest dogs. Propranolol strongly inhibited the effect of TA-870 on LVdP/dt/Pmax. It also inhibited the effects of TA-870 on TPR and CO to a lesser extent, and the remaining effects were almost completely inhibited by an additional treatment with the dopamine blocker, RS-sulpiride. In conclusion, TA-870 increased myocardial contractility and output by the enteral route, and the latter effect was produced at lower doses with the help of peripheral vasodilation due to the activation of dopamine receptors.     

The availability of carfecillin and its phenol moiety in rat and dog

1. Studies have shown that hydrolysis of carfecillin to carbenicillin and phenol in vitro occurs in blood, liver and gut tissues of rat and dog. Extremely rapid hydrolysis was observed in the blood and liver of the rat.

2. Absorption studies in intestinally-perfused rats showed that following administration of either [¹⁴C]phenol or [phenol-¹⁴C]carfecillin, the half-life values of radioactivity in the intestinal lumen were 6?min and 47?min respectively.

3. Following oral administration of phenol to rats and dogs at 300?mg/kg and 40?mg/kg respectively, maximum plasma concn. of phenol were 26 μg/ml and 7.8 μg/ml. However, following oral administration of carfecillin to rats and dogs at dose levels of 3000 and 800?mg/kg respectively, no significant amounts of free phenol or intact carfecillin were detected (< 1 μg/ml). The very low concentrations of phenol found after carfecillin administration and the concomitant absence of acute phenol toxicity is explained by the slow absorption of carfecillin and its slow hydrolysis to phenol in the gut lumen.

4. In the dog, phenol which enters the portal circulation as carfecillin appears to undergo significant ‘first pass’ metabolism by the liver, while no such effect was observed if free phenol was administered.