Stereoselectivity of idarubicin reduction in various animal species and humans

1. The (13S)-dihydro derivative of idarubicin, (13S)-idarubicinol, is the major urinary metabolite of idarubicin in humans. Idarubicinol epimers were quantified by h.p. 1.c. in urine from rats, mice, rabbits, dogs and man after i.v. administration of idarubicin, and in man after oral dosing. The (13R)- and (13S)-epimers of idarubicinol were determined in rat bile.

2. After i.v. injection of idarubicin. (13R)-idarubicinol was not detectable in mice and rabbit urine and no more than 0.5% of the dose was present in the urine of other species. In man, the proportion of (13R)-idarubicinol in total idarubicinol was similar after i.v. (4.1%) and oral (3.8–5.0%) administration of idarubicin; the same applies to rat bile and urine.

3. Reduction of idarubicin in vivo is dependent upon ketone reductases, and proceeds more stereoselectively than that of most ketones giving rise to the (13S)-epimer almost exclusively. The high stereospecificity in idarubicin reduction might result from chiral induction due to the presence of asymmetric centres near to the carbonyl group in idarubicin.     

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration

1. Z-7760 (S(-)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. 3H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 microCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total 3H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma 3H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma 3H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given 3H-Z-7760 p.o. (0.4 mg and 40 microCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with 3H-Z-7760 (0.4 mg and 400 microCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% 3H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 microCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.     

Pharmacokinetics of idarubicin (4-demethoxydaunorubicin; IMI-30; NSC 256439) following intravenous and oral administration in patients with advanced cancer.

The plasma pharmacokinetics of idarubicin (4-demethoxydaunorubicin) were studied in 20 patients with advanced malignant disease after intravenous (21 occasions) and oral (14 occasions) administration. Idarubicin plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters calculated for the intravenous plasma drug concentration, time data revealed a terminal half-life of 12.9 +/- 6.0 h (mean +/- s.d.), clearance 98.7 +/- 47.3 1 h-1 m-2 and volume of distribution 1533 +/- 536 1 m-2. A bi-exponential equation corresponding to a two compartment open model best fitted the data. Half-life and clearance were not significantly different following oral administration. Bioavailability of oral idarubicin was 0.29 +/- 0.20 (mean +/- s.d.). There was a wide range of bioavailability between and within subjects. Plasma concentrations of idarubicinol (the only metabolite detected) rapidly exceeded those of the parent drug, and exposure to this metabolite was greater than to the parent drug. The mean half-life of idarubicinol was not significantly different after i.v. (63.1 +/- 28.2 h) and oral (45.8 +/- 16.0 h) administration. Much larger amounts of this metabolite were formed following the oral route of administration. This may have implications for the clinical use of this drug as idarubicinol may have appreciable cytotoxic activity.     

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration

1. Z-7760 (S(?)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy- 1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. ³H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 μCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total ³H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma ³H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma ³H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given ³H-Z-7760 p.o. (0.4?mg and 40 μCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with ³H-Z-7760 (0.4?mg and 400 μCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% ³H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100?mg/kg, 40 μCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.     

Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man.

1. Pharmacokinetics of dofetilide were studied in man, dog, rat and mouse after single i.v. and oral doses of dofetilide or 14C-dofetilide. 2. Dofetilide was absorbed completely in all species. Low metabolic clearance in man resulted in complete bioavailability following oral administration. Higher metabolic clearance in rodents, and to a lesser extent dogs, resulted in decreased bioavailability because of first-pass metabolism. 3. Following i.v. administration, the volume of distribution showed only moderate variation in all species (2.8-6.3 l/kg). High plasma clearance in rodents resulted in short half-life values (mouse 0.32, male rat 0.5 and female rat 1.2 h), whilst lower clearance in dog and man gave longer terminal elimination half-lives (4.6 and 7.6 h respectively). 4. After single i.v. doses of 14C-dofetilide, unchanged drug was the major component excreted in urine of all species with several metabolites also present. 5. Metabolites identified in urine from all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetilide. 6. After oral and i.v. administration of 14C-dofetilide to man, parent compound was the only detectable component present in plasma and represented 75% of plasma radioactivity. No single metabolite accounted for greater than 5% of plasma radioactivity.     

The metabolic fate of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in rats after intravenous and oral administration. I. Disposition and metabolic profiling

1. The disposition and metabolic profiling of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin(I), a dopamine agonist, were studied in anaesthetized rats after i.v. administration and in non-anaesthetized rats after i.v. and oral dosing. No major differences due to narcosis were observed. 2. Independent of dosing route or anaesthetic, clearance of I was rapid. Bile was the main route of excretion, accounting for 88% dose, compared with 9% in urine. 3. Drug metabolic profiling revealed that I is almost completely metabolized before elimination; less than 0.5% total radioactivity in bile and urine was due to parent compound. 4. The biliary metabolic profiles after i.v. and oral administration were similar. One major metabolite was detected, accounting for 50% (i.v.) or 65% (oral) dose. The major biliary metabolite was identified as the glucuronide of I. 5. Urinary metabolic profiles were quantitatively different from those of bile. After i.v. administration one major metabolite was detected in urine, but this was not the major biliary metabolite. After oral administration, the major urine metabolite was the same as the major biliary metabolite. These differences can be explained by first-pass gastro-intestinal metabolism.     

The Disposition and Metabolism of Amodiaquine in Small Mammals

1. 7-Chloro-4-(3′-diethylamino-4′-hydroxyanilino)quinoline (amodiaquine) labelled with ¹⁴C has been synthesized and administered in single doses to rats including bile-duct-cannulated rats, to guinea-pigs and to mice, by oral or parenteral routes.

2. Amodiaquine was extensively and rapidly absorbed from the rat intestinal tract. Excretion of total radioactivity from rats and guinea pigs was slow and prolonged and was <50% dose in 9 days. Excretion of ¹⁴C was predominantly in faeces of rats after oral and i.p. dosage, and guinea-pigs after i.p. dosage. Radioactivity in rat and guinea-pig urine was <11% dose.

3. Biliary excretion of ¹⁴C following oral or i.v. dosage to rats was 21% dose in 24?h.

4. Amodiaquine was extensively metabolized and conjugated with <10% dose excreted unchanged in urine or bile. Two major basic metabolites in rat urine were tentatively identified as the mono- and bis-desethyl amines.

5. 7-Chloro-4-(4′-diethyl-1′-methylbutylamino)quinoline (chloroquine) was excreted largely unchanged in urine of rats after oral or parenteral administration of single doses, with <5% dose excreted in rat bile in 24?h.     

Glutathione conjugation of the alpha-bromoisovaleric acid enantiomers in the rat in vivo and its stereoselectivity. Pharmacokinetics of biliary and urinary excretion of the glutathione conjugate and the mercapturate

The glutathione (GSH) conjugation of (R)-and (S)-alpha-bromoisovaleric acid (BI) in the rat in vivo, and its stereoselectivity, have been characterized. After administration of racemic [1-14C]BI two radioactive metabolites were found in bile: only one of the possible diastereomeric BI-GSH conjugates, (R)-I-S-G (35 +/- 2% of the dose), and an unidentified metabolite "X" (6 +/- 1%). In urine, only one of the possible BI-mercapturates, (R)-I-S-MA (14 +/- 1%), minor unidentified polar metabolites (5 +/- 1%) and unchanged BI (13 +/- 2%) were excreted. When (R) or (S)-BI were administered separately, the same metabolites were found. However, a ten-fold difference in excretion half lives of the biliary metabolites was observed following (S)-and (R)-BI administration, (S)-BI being more rapidly excreted. The excretion of the mercapturate in urine shows the same difference in excretion rate: its half life after administration of (R)-BI was more than 10 times longer than after a dose of (S)-BI. More of the dose of (S)-BI was excreted after 5 hr in bile and urine: 58% and 23% respectively for (S)- and (R)-BI. Therefore, a pronounced stereoselectivity in GSH conjugation exists for the (R) and (S) enantiomers of BI in the rat in vivo, which is a major determinant of their pharmacokinetics. The results suggest that (slow) inversion of the chiral centre of BI occurred in the rat in vivo.     

The Biliary Elimination and Enterohepatic Circulation of Ibuprofen in Rats

The biliary and urinary excretion of ibuprofen and its metabolites were determined in rats after intravenous and peroral administration of 25 and 100 mg/kg of the drug. Within 24 hours 48% of the low i.v. dose and 59% of the high i.v. dose were eliminated via bile as ibuprofen and its metabolites. Following oral administration 40 to 41% of the dose were recovered in bile, whereas 16 to 32% of the dose were eliminated in urine, resulting in an overall drug recovery of 66 to 79% within 24 hours. Upon infusion of bile containing ibuprofen and its metabolites into the duodenum substantial enterohepatic cycling of the drug occurred in the rat.     

Pharmacokinetics of ethopropazine in the rat after oral and intravenous administration

The pharmacokinetics of the anticholinergic drug ethopropazine (ET) have been studied in the rat after intravenous (i.v.) and oral administration. After i.v. doses of 5 and 10 mg/kg ET HCl, mean +/- S.D. plasma AUC were 9836 +/- 2129 (n = 4 rats) and 13096 +/- 4186 ng h/mL (n = 5 rats), respectively. The t1/2 after 5 and 10 mg/kg i.v. doses were 17.9 +/- 3.3 and 20.9 +/- 6.0 h, respectively. The Cl and V(dss) after 5 mg/kg i.v. doses were 0.48 +/- 0.10 L/h/kg and 7.1 +/- 2.3 L/kg, respectively. Statistically significant differences were present between the 5 and 10 mg/kg dose levels in Cl and V(dss). Oral administration of 50 mg/kg ET HCl (n = 5 rats) yielded mean AUC of 2685 +/- 336 ng h/mL. Mean plasma C(max), t(max) and t1/2 after oral doses were 236 +/- 99 ng/mL, 2.2 +/- 1.4 h and 26.1 +/- 5.4 h, respectively. Less than 1% of the dose was recovered unchanged in urine and bile. Ethopropazine is extensively distributed in the rat, and has relatively slow Cl in relation to hepatic blood flow in the rat. The drug appears to be extensively metabolized in the rat, and nonlinearity is present between the 5 and the 10 mg/kg i.v. doses. The drug displayed poor bioavailability (< 5%) after oral administration.     

Pharmacokinetic characteristics and hepatic distribution of IH-901, a novel intestinal metabolite of ginseng saponin, in rats

We investigated the pharmacokinetic characteristics of 20- O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), a metabolite that is formed by intestinal bacteria, after its intravenous (i.v.) or oral administration in rats. We developed an LC/MS/MS-based method to analyze IH-901 levels in plasma, bile, urine and tissue homogenates and validated its use in a pharmacokinetic study. After i.v. administration of 3 - 30 mg/kg IH-901, it disappeared rapidly from the plasma at alpha phase followed by slow disappearance at beta phase (t(1/2,)(alpha) of 0.042 - 0.055 h and t (1/2,)(beta) of 6.98 - 10.6 h, respectively). The oral route slightly prolongs IH-901 plasma levels (terminal phase t(1/2) of 26.1 h) yet leads to a bioavailability of only 4.54 %. Of the various organs tested, the liver contained the majority of the i.v. bolus or orally administered IH-901, and liver IH-901 levels shortly after i.v. administration were 6-fold higher than the initial plasma concentration. The R(h) (hepatic recovery ratio) was calculated to be 0.417, and the uptake clearance (CL(uptake)) for i.v. administered IH-901 was 0.401 mL.min(-1).g liver(-1). Additionally, IH-901 is mostly excreted into the bile, since 40.5 % of the i.v.-administered dose (30 mg/kg) was recovered in the bile within 6 h, and only 15 % was found in the urine. Moreover, at steady state after i. v. infusion of IH-901, C(ss,liver) was about 11.3-fold higher than C(ss,plasma), whereas C(ss,bile) was about (1/2)-fold lower than C(ss,liver). These results indicated that the liver is largely responsible for removing IH-901 from the circulation. Oral administration of IH-901 leads to a low bioavailability; thus, the parenteral route may be the suitable way to deliver IH-901 for clinical applications.     

Studies on pharmacokinetics and biotransformation of reproterol in animal and man (author's transl)

Investigations on the pharmacokinetics and biotransformation in the rat, dog, rabbit and in humans were performed with 3H-or 14C-labelled 7-(3-[2-(3,5-dihydroxyphenyl)-2-hydroxy-ethlamino]-propyl)-theophylline (reproterol, Bronchospasmin). Following i.v. administration of reproterol, a similar course of the plasma levels as shown in both rat and dog. After oral administration to the rat, elimination occurs within 2 h following application; in the dog, however, a relatively constant plasma level persists for up to 24 h, which is then reduced during an elimination half-life of 12.4 h. Following i.v. as well as oral administration to the rabbit, phases of distribution and elimination persist over a considerable length of time. Plasma levels following oral administration remain relatively constant during a time period of 8--30 h, after which they decrease with a half-life of 70 h. Renal elimination in the dog and rabbit after i.v. application seems to be the main route of excretion (dog 57%, rabbit 66%), while in the rat there is 58% fecal elimination. Absorption ratios following oral administration amount to 13% in the rabbit and 18% in the rat and dog. The absorption ration in the rat following intratracheal application reaches 90%. This was particularly important in view of the anticipated use of reproterol as an aerosol. Tests on the quantitative organic distribution further showed that in the rat, the lund tissue has a particular affinity to reproterol. In man following i.v. administration, reproterol is rapidly distributed and eliminated. The highest plasma level reached within 2 h after oral administration, correlates well with the initial plasma level following i.v. administration. A great similarity was shown for the reproterol metabolism in rat, dog, rabbit and man. With complete metabolization, the same main metabolite is always formed.     

The metabolism in animals and man of oxmetidine--a new histamine H2-receptor antagonist

The absorption, distribution, metabolism and excretion of [14C]oxmetidine in rat, dog and man has been studied following both i.v. and oral administration. Excretion is rapid and essentially complete in all three species. The biliary route is predominant. Distribution of radioactivity is widespread although none is seen in the brain. Metabolite patterns in urine from rat, dog and man have been compared by thin-layer chromatography. Metabolite patterns in urine and bile from rat and dog have been compared by high pressure liquid chromatography. Six major metabolites have been isolated and identified including two O-glucuronides and one N-glucuronide.     

Metabolism and disposition of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in conscious monkeys after subsequent i.v. oral, and ocular administration

The metabolism of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) was investigated in conscious monkeys after subsequent i.v., oral, and ocular administration. The administration of the drug caused some physiological effects, such as bradycardia and sedation of the monkeys. During a collection period of 120 hr, on average 83% was recovered after iv administration and 90% after p.o. dosing. After i.v. administration, 44% was excreted in the bile, as compared to 38% in the urine and about 1% in the feces. After oral administration, bile is the major excretion route, accounting for about 60% of the dose, as compared to 25% in the urine and about 5% in the feces. After ocular administration, on average 62% was recovered after 7 hr, excreted in bile and urine in about equal amounts. All percentages given above reflect the total amount of radioactivity recovered, thus comprising the unchanged drug plus various metabolites. After all three dosing routes, N-0437 was metabolized almost completely prior to elimination. Direct glucuronidation of the phenolic group proved to be the major metabolic pathway of N-0437, comprising about 44% of the dose after i.v. and ocular administration and 72% after oral dosing. Hydroxylation of N-0437 at the position ortho to the phenolic group present yielded a catechol intermediate, which was excreted as a glucuronide and accounted for about 10% of the dose. In the monkey, a clear regioselective preference towards glucuronidation at the 6-position was observed. Besides the glucuronide, the sulfoconjugate of N-0437 was a major metabolite after i.v. and ocular administration, accounting for about 15% of the dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism of pamaqueside, a cholesterol absorption inhibitor, in Long-Evans rat: effect of bile duct cannulation on absorption

The metabolism of pamaqueside, a cholesterol absorption inhibitor, was studied in the bile duct cannulated and non-cannulated rat after an oral dose (100 mg/kg) and an i.v. dose (6 mg/kg) of [14C]pamaqueside. Faeces was the major route of excretion in all rat. Only 0.1% of the radioactivity was recovered in the urine of the non-cannulated rat. In contrast, approximately 17% of the total dose was recovered in the bile and urine in the bile duct cannulated rat. Following an i.v. dose, an almost equal percentage of radioactivity was excreted in the bile and urine of the bile duct cannulated rat. 3. The aglycone (M1) was the major metabolite in rat and was present in greater amounts in the faeces of the bile duct cannulated rat. The structural elucidation of metabolites in the bile and urine indicated that M1 was metabolized oxidatively via a novel ring opening, and the oxidative metabolites further underwent sulphate conjugation. The oxidative ring opening of pamaqueside (the cellobioside ring intact) was also observed following an i.v. dose to rat suggesting that oxidative ring opening was the major route of metabolism of saponins, at least in rat. The study demonstrated that the absorption and metabolism of pamaqueside was altered by surgical cannulation of rat.     

Pharmacokinetics and tissue distribution of idarubicin-loaded solid lipid nanoparticles after duodenal administration to rats

Idarubicin-loaded solid lipid nanoparticles (IDA-SLN) and idarubicin in solution were prepared and the two formulations were administered to rats, either by the duodenal route or intravenously (iv). The aim of this research was to study whether the bioavailability of idarubicin can be improved by administering IDA-SLN duodenally to rats. Idarubicin and its main metabolite idarubicinol were determined in plasma and tissues by reversed-phase high-performance liquid chromatography. The pharmacokinetic parameters of idarubicin found after duodenal administration of the two formulations were different: area under the curve of concentration versus time (AUC) and elimination half-life were approximately 21 times and 30 times, respectively, higher after IDA-SLN administration than after the solution administration. Tissue distribution also differed: idarubicin and idarubicinol concentrations were lower in heart, lung, spleen, and kidneys after IDA-SLN administration than after solution administration. The drug and its metabolite were detected in the brain only after IDA-SLN administration, indicating that SLN were able to pass the blood-brain barrier. After iv IDA-SLN administration, the AUC of idarubicin was lower than after duodenal administration of the same formulation. Duodenal administration of IDA-SLN modifies the pharmacokinetics and tissue distribution of idarubicin. The IDA-SLN act as a prolonged release system for the drug.     

On the pharmacokinetics and metabolism of propiverine in man

The pharmacokinetics of 14C-propiverine was studied in 13 volunteers and in 2 patients after a single i.v. injection of 5 mg or after oral administration of 15 mg. To each dose 1.11 MBq 14C-propiverine was added. The radioactivity measured in plasma, urine (and bile fluid), and the metabolites were estimated by an extraction procedure together with TLC and radiochromatography. Propiverine was eliminated from the plasma with a half-life time (t0.5) of 4.1 h (i.v. and per os), while the plasma radioactivity decreased with a t0.5 of 21.2 (i.v.) or 10.4 h (per os). Within 4 days, 84.5 (i.v.) or 53.5% (per os) of the administered radioactivity was excreted in urine. The absorption of radioactivity of propiverine amounted to 84.5%, while the amount of available propiverine was only 48.9%. In two patients with cannulated ductus choledochus, 21.5 or 14.7% of the administered radioactivity was excreted within 2 days. The metabolic pattern of plasma, urine and bile fluid mainly consisted of amine oxides, substances oxidized in the propyl side chain, desalkylated metabolites, substances with a N-demethylated piperidino group or with ester cleavage, and glucuronide conjugates. Unchanged propiverine appeared in plasma, urine and bile at about 6 to 8% of the administered dose.     

Interspecies comparison of the metabolic pathways of perindopril, a new angiotensin-converting enzyme (ACE) inhibitor

1. The metabolism of perindopril (non-thiol angiotensin-converting enzyme inhibitor) was studied in rat, dog and monkey after single oral and i.v. administration of 14C-perindopril, and in man after a single oral dose. 2. Six biotransformation products of perindopril from urine, faecal and plasma samples (bile only for rats) were identified. 3. The main route of biotransformation in all species is the hydrolysis of the carboxylic ethyl ester side-chain, with the formation of perindoprilate, the active metabolite. 4. A minor route of biotransformation led to the acyl glucuronides of perindopril and perindoprilate. 5. Internal dehydration of perindopril and perindoprilate into cyclic lactam structures occurs. This route of metabolism is of minor importance except in humans.     

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.