Metabolism and disposition of 14C-granisetron in rat,dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of ¹⁴C-granisetron, a novel 5-HT₃ antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration.

2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species.

3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0·25 and 5 mg/kg in rat and 0·25 and 10mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man.

4. In rat and dog, 35–41% of the dose was excreted in urine and 52–62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5–25% of dose).

5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

Absorption and disposition of ranitidine hydrochloride in rat and dog

1. The pharmacokinetics of ranitidine were studied in the male beagle dog at a dose level of 50 mg (intravenous) or 5 mg/kg (oral).

2. After intravenous administration, Cl_p was moderate (10·4 ml/min/kg) with Cl_r accounting for approximately 30% of total clearance. Vd_area was 3·51/kg, resulting in a t_1/2 of approximately 4 h.

3. After oral administration, F was good (73%) with peak plasma concentrations of ranitidine (2 μg/ml) achieved within 0·5–1 h after dosing. t_1/2 (4·1 h) was similar to that observed after intravenous administration.

4. The absorption, metabolism and excretion of [¹⁴C]-ranitidine were studied in rat and dog after oral administration at a dose level of 50 mg/kg.

5. Urinary excretion was the major elimination pathway for radioactive drug-related material in both species (62–75% of the dose). Unchanged ranitidine was the major radioactive component in both rat and dog urine (0–24 h), accounting for approximately 40% of the dose in each case.

6. In dog, ranitidine undergoes N-oxidation (～ 30% of dose) whereas in rat, N-oxidation, S-oxidation, N-demethylation and oxidative deamination are all evident, with each metabolite accounting for <6% of the dose.

7. Two previously unreported metabolites of ranitidine were identified in rat urine using newly developed hplc and lc/ms methods. These metabolites result from single and di-N-demethylation of ranitidine and accounted for 4 and 1% of the dose respectively.     

Biotransformation and mass balance of faldaprevir,a hepatitis C NS3/NS4 protease inhibitor in rats

Abstract

1.?The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2?mg/kg intravenous or 10?mg/kg oral administration of [¹⁴C]-faldaprevir.

2.?Following intravenous dosing, the terminal elimination t_1/2 of plasma radioactivity was 1.75?h (males) and 1.74?h (females). Corresponding AUC_0–∞, CL and V_ss were 1920 and 1900?ngEq?·?h/mL, 18.3 and 17.7?mL/min/kg and 2.32 and 2.12?mL/kg for males and females, respectively.

3.?After oral dosing, t_1/2 and AUC_0–∞ for plasma radioactivity were 1.67 and 1.77?h and 11?300 and 17?900 ngEq?·?h/mL for males and females, respectively.

4.?In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively.

5.?Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism.

6.?Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6?h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.     

Disposition and Metabolic Fate of Tiaramide Hydrochloride,a New Anti-inflammatory Agent,in the Rat

1. A new non-steroidal anti-inflammatory agent, 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)[¹⁴C]acetyl]- 1-piperazine-ethanol hydrochloride (tiaramide hydrochloride) was rapidly absorbed after oral administration, reaching peak serum concn. in 20 min, with a half-life of 2·7 h. After intravenous injection the concn. of tiaramide decreased biphasically with half-lives of 0·2 and 1·3 h.

2. The metabolism of tiaramide, both in vivo and in vitro with rat liver 10 000 g supernatant fraction, gave three major metabolites identified as 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR), 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineacetic acid (TRAA), and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineethanol 1-oxide (TRNO). The major serum metabolites were TRAA and TRNO.

3. After oral administration, unchanged tiaramide was found in high concn. in liver, kidney and lung. Tissue levels of tiaramide were 4–6 times higher than serum. Distribution of tiaramide in inflammatory tissue was also demonstrated. The major tissue metabolite was DETR and its concn. was 20–40 times higher in tissue than in serum.

4. Urinary excretion was almost complete within 24?h after oral administration. The major urinary metabolites were TRAA and TRNO.

5. Repeated administration of tiaramide did not alter the metabolism of tiarsmide.     

Excretion and Biotransformation of Carboxymethyl-cysteine in Rat,Dog, Monkey and Man

1. Following an oral dose of S-carboxymethyl[³⁵S]cysteine, monkey (rhesus and African green), rat, dog, and man excreted 77, 88, 95, and 100% respectively of the ³⁵S radioactivity in urine and 7·0, 2·5, 0·7, and 0·3% in faeces during a 3 to 4 day period.

2. The principal drug-related components excreted were unchanged carboxymethylcysteine, dicarboxymethyl sulphide and inorganic sulphate.

3. Rat, dog, and man excreted primarily dicarboxymethyl sulphide and unchanged carboxymethylcysteine and no inorganic sulphate (rat, 7%).

4. Monkey excreted largely inorganic sulphate, moderate amounts of dicarboxymethyl sulphide and a trace of unchanged drug.     

PHARMACOKINETICS AND TOXICOKINETICS OF AN ORALLY ACTIVE TRIPEPTIDE,IRI-695, IN ANIMALS

Pharmacokinetics and toxicokinetics of IRI-695, a tripeptide, were investigated in the rat, rabbit, dog, and monkey. Tissue distribution and excretion of [¹⁴C]IRI-695 were determined in the rat. Following a single intravenous (IV) injection, the elimination half-life (t_1/2) of IRI-695 in the rabbit, dog, and monkey was similar (about 65 min) and approximately four times that in the rat (15 min). This difference in t_1/2 can be attributed to about four times higher clearance of the drug in rats (11·2 mL min⁻¹ kg ⁻¹). The volume of distribution (V_ss) in these four species, 132–234 mL kg⁻¹, suggested negligible preferential distribution of IRI-695 to body tissue. After a 5 mg kg⁻¹ oral dose, the absolute bioavailability of IRI-695 was 2·0% in rats and 3·1% in dogs. However, systemic drug exposure in the dog was about five to 10 times that in the rat, which is related to the slower clearance of the peptide in the dog. Toxicokinetic studies in the rat and dog indicated linear kinetics and systemic exposure of IRI-695 up to 300 mg kg⁻¹ d⁻¹ oral doses throughout the 28 d toxicity study. Accumulation of the drug after the repeated oral dosing was negligible. After a single 0·10 mg kg⁻¹ ]¹⁴C[IRI-695 IV injection in rats, almost all of the radioactivity administered was excreted in urine within 24 h postdose.     

Species Differences in Metabolism of Tiaramide Hydrochloride,a New Anti-inflammatory Agent

1. Urinary excretion of the radioactivity in 24?h after oral administration of [¹⁴C]tiaramide hydrochloride was 67% of the dose in mice, 59% in rats, 41% in dogs and 74% in monkeys.

2. The serum half-lives of tiaramide after intravenous administration were approximately 0·2?h in mice, 0·8?h in rats and 0·5?h in dogs.

3. Marked species variations were noted in the composition of metabolites in the serum and urinary radioactivity. The major metabolites found were 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR) and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineacetic acid (TRAA) in mice, TRAA and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-pipera-zineethanol 1-oxide (TRNO) in rats, TRNO and tiaramide-O-glucuronide (TR-O-Glu) in dogs, and TRAA and TR-O-Glu in monkeys.

4. The binding of tiaramide to plasma protein of the various species of animals and human was about 24–34% and the extent of the binding of tiaramide to human plasma protein was independent of drug concentration within the range of 1–100 μM.     

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.     

Pharmacokinetics of gefitinib,an epidermal growth factor receptor tyrosine kinase inhibitor,in rat and dog

1.?The pharmacokinetics of gefitinib and its metabolites in rat and dog were investigated in preclinical studies conducted to support the safety evaluation and clinical development of gefitinib, the first EGFR tyrosine kinase inhibitor approved for the treatment of non-small-cell lung cancer.

2.?Following intravenous dosing (5?mg?kg^?1), gefitinib plasma half-life was 3–6?h in rats and dogs, although studies using a more sensitive HPLC-MS assay produced longer estimates of half-life (7–14?h).

3.?In these studies, plasma clearance was high (male rat: 25?ml?min^?1?kg^?1; female rat: 16?ml?min^?1?kg^?1; male dog: 16?ml?min^?1?kg^?1), as was the volume of distribution (8.0–10.4?l?kg^?1 in rat; 6.3?l?kg^?1 in dog), and exposure in female rats was double that in males.

4.?Following administration of [¹⁴C]-gefitinib, concentrations of radioactivity in plasma exceeded gefitinib throughout the profile, indicating the presence of circulating metabolites in both rat and dog.

5.?An HPLC-MS assay was developed to measure concentrations of gefitinib and five potential metabolites in plasma. All five metabolites were detected in the rat, but at levels much lower than gefitinib. In the dog, exposure to gefitinib and M523595 was similar, with much lower concentrations of M537194 and only trace levels of the other metabolites. This profile of metabolites is similar to that observed in man.     

Absorption,metabolism and excretion of tamsulosin hydrochloride in man

1. The absorption, excretion and metabolism of tamsulosin hydrochloride (TMS), a potent α₁-adrenoceptor blocking agent, were studied in four healthy male subjects after a single oral administration of ¹⁴C-TMS at a dose of 0·2?mg.

2. Plasma and blood radioactivity concentrations attained peak levels (C_max) within 1?h after dosing and then declined biphasically. Mean terminal elimination half-lives were 11·8?h for plasma and 9·1?h for blood. The respective mean area under the radioactivity concentration-time curves (AUC_0-∞) were 122·8 and 57·8 ng equivalents h/ml.

3. Mean plasma C_max of unchanged TMS was 13·0 ng/ml. Plasma levels of TMS declined biphasically. Mean terminal elimination half-life and AUC_0-∞ were 8·4?h and 90·3 ng h/ml. The percentage of unchanged TMS to total radioactivity was 91% for C_max and 74% for AUC_0-∞ indicating small amounts of metabolites in plasma.

4. By 1 week post-dosing, 76·4% of the administered radioactivity was recovered in urine and 21·4% in faeces. The major part of radioactivity excreted in urine was recovered within the first 24?h (62·2% of the dose).

5. Unchanged TMS and 11 metabolites in 0-24-h urine samples were quantified. TMS accounted for 8·7% of the dose. Extensive excretion of the sulphate of the O-deethylated metabolite (M-1-Sul) and o-ethoxyphenoxy acetic acid (AM-1) was seen, accounting for 15·7 and 7·5% of the dose respectively.     

The Metabolism of Terbutaline in Dog and Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been studied in dog after oral, intravenous and subcutaneous administration and in rat after oral and intravenous administration. In 3–4 days the dog excreted 75% of the dose in the urine after oral administration and more than 90% after intravenous or subcutaneous administration; the remainder was in the faeces. The rat in 24 h excreted about 13% in the urine and 61% in the faeces after oral administration and 48% in the urine and 35% in the faeces after intravenous administration.

2. After oral administration of [³H]terbutaline, the time course of radioactivity concentration was the same in lung, heart and serum; low levels of unchanged drug were found in all tissues. After intravenous administration, the concentration of unchanged drug was higher in lung and heart than in serum.

3. In dog, 1·7% of an intravenous dose was excreted into bile in 6 h. In rat, about 37% of the dose was recovered in the bile during 12 h.

4. Enzymic hydrolysis of urine showed that terbutaline is metabolized by conjugation, forming a glucuronide in rat but probably a sulphate in dog.     

Disposition of the opioid antagonist,nalmefene, in rat and dog

1. The disposition of nalmefene in rat and dog was studied using in vitro and in vivo methodology. In vitro metabolite profiles were obtained following incubation of nalmefene with liver microsomes and biological fluids were assayed to profile in vivo metabolites. Characterization of metabolites was accomplished using hplc, co-chromatography with synthetic standards, or LC/MS.

2. In rat, tissue distribution and metabolite plasma concentration-time data were obtained following intravenous bolus dosing of nalmefene.

3. The results indicate that the primary phase I metabolite of nalmefene from liver microsome incubations was the N-dealkylated metabolite, nornalmefene. Quantitative metabolite production was rat ? dog. In vivo, nornalmefene glucuronide was the major metabolite in rat urine, whereas nalmefene glucuronide(s) were predominant in dog urine.

4. More than 90% of the radioactive dose was recovered in the rat excreta and tissues 24?h after an intravenous bolus dose of ¹⁴C-nalmefene, with no apparent organ-specific retention of radioactivity.

5. Pharmacokinetic analysis of the rat plasma metabolite data indicated that terminal half-lives for nalmefene and nornalmefene were comparable (～ 1?h). However, C_max and AUC of nornalmefene were ≤ 7% that of corresponding nalmefene values.     

Absorption,distribution and excretion of the new thienopyridine agent prasugrel in rats

Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, ¹⁴C-prasugrel or prasugrel was administered to rats at a dose of 5?mg?kg^–1. After oral and intravenous dosing, the values of AUC_0–∞ of total radioactivity were 36.2 and 47.1?µg?eq.?h?ml^–1, respectively. Oral dosing of unlabeled prasugrel showed the second highest AUC_0–8 of the active metabolite of six metabolites analyzed. Quantitative whole body autoradiography showed high radioactivity concentrations in tissues for absorption and excretion at 1?h after oral administration, and were low at 72?h. The excretion of radioactivity in the urine and feces were 20.2% and 78.7%, respectively, after oral dosing. Most radioactivity after oral dosing was excreted in bile (90.1%), which was reabsorbed moderately (62.4%). The results showed that orally administered prasugrel was rapidly and fully absorbed and efficiently converted to the active metabolite with no marked distribution in a particular tissue.     

Pharmacokinetics of antofloxacin hydrochloride,a novel fluoroquinolone,after single-dose intravenous administration in healthy Chinese male volunteers

1. The purpose of the study was to evaluate the pharmacokinetic characteristics of a single, intravenous dose of antofloxacin hydrochloride in healthy Chinese male volunteers.

2. Twelve subjects were randomly assigned to groups that received a single, intravenous dose of 200, 300, or 400?mg antofloxacin hydrochloride in a three-way crossover design study. The serum and urine concentrations of antofloxacin were then assayed with high-performance liquid chromatography (HPLC). Major pharmacokinetic parameters and urine excretion were obtained up to 96?h after administration.

3. All three dosages were well tolerated. No clinically adverse reactions or abnormal laboratory results were detected.

4. After single-dose intravenous administration, antofloxacin hydrochloride exhibited linear pharmacokinetic characteristics with increasing dosages. The C_max for groups treated with 200, 300, or 400?mg dosages were 2.05?±?0.38, 3.01?±?0.60, and 3.80?±?0.78?mg l^?1, respectively; the areas under the curve from zero to infinity (AUC_0–∞) were 25.14?±?2.95, 37.63?±?5.42, and 53.87?±?9.48?mg l^?1·h, respectively. The t_1/2β was around 20?h; and the urinary excretion was measured as being from 58% to 60% within 96?h.

5. Based on these results, 300?mg of antofloxacin hydrochloride administered once daily is the dose suggested for further investigation in multiple-dose administration studies.

     

Absorption,Excretion and Metabolism of a New Dihydropyridine Diester Cerebral Vasodilator in Rats and Dogs

1. After oral administration of [¹⁴C]dihydropyridine diester, the plasma concn. of radioactivity was similar in rats and dogs, reaching a maximum at 0·5 to 1?h and decreasing with a half life of about 3·5 h. The plasma concn. of unmetabolized drug in dogs was 10 times higher than in rats. Radioactivity in rat tissue was high in liver, kidney and lung after both oral and intravenous administration.

2. In both species, 66–72% of radioactivity was excreted in faeces and 23–29% in urine in 48?h, regardless of the route of administration. Biliary excretion in rats after oral dosage amounted to 65%.

3. Eight metabolites were identified from urine of dogs and rats. They were derived from one or several of the following pathways: I, debenzylation of the N-benzyl-N-methylaminoethyl side chain; II, reduction of the 3-nitro group on the phenyl substituent; III, oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine; IV, oxidative removal of the N-benzyl-N-methylamino group yielding a carboxylic acid; V, hydrolysis of the N-benzyl-N-methylamino-ethyl ester to the corresponding carboxylic acid; VI, hydroxylation of the 2-methyl group of the 1,4-dihydropyridine ring to hydroxymethyl.     

Determination of dihydromyricetin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study

Context: The pharmacokinetics properties of dihydromyricetin (DHM) are still unknown.

Objective: This study investigates the pharmacokinetic characteristics of DHM using a sensitive and reliable LC-MS/MS method.

Materials and methods: A rapid and sensitive LC-MS/MS method was developed for the determination of DHM in male Sprague–Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (2?mg/kg) and the oral group (20?mg/kg). Blood samples (250?μL) were collected at designated time points and analyzed using this method. The pharmacokinetic parameters were calculated using DAS 3.0 pharmacokinetic software.

Results: The calibration curve was linear within the range of 0.5–200?ng/mL (r?>?0.998) with the lower limit of quantification at 0.5?ng/mL. After the intravenous injection, DHM reached a maximum concentration of 165.67?±?16.35?ng/mL, and t_1/2 was 2.05?±?0.52?h. However, DHM was not readily absorbed and reached C_max 21.63?±?3.62?ng/mL at approximately 2.67?h following the oral administration of DHM, and t_1/2 was 3.70?±?0.99?h. The MRT for the intravenous group and the oral group were 2.62?±?0.36 and 5.98?±?0.58?h, respectively. The AUC_(0-t) for the intravenous group and the oral group were 410.73?±?78.12 and 164.97?±?41.76?ng·L/mL, respectively, so the absolute bioavailability of DHM was 4.02% which was poor.

Discussion and conclusion: The results indicated that the bioavailability was poor. Further work needs to be conducted to investigate the reason for poor bioavailability and improve this situation.     

Disposition,metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration

Abstract

1. The pharmacokinetics and disposition of delafloxacin was investigated following a single intravenous (300?mg, 100?µCi) dose to healthy male subjects.

2. Mean C_max, AUC_0–∞, T_max and t_1/2 values for delafloxacin were 8.98?µg/mL, 21.31?µg?h/mL, 1?h and 2.35?h, respectively, after intravenous dosing.

3. Radioactivity was predominantly excreted via the kidney with 66% of the radioactive dose recovered in the urine. Approximately 29% of the radioactivity was recovered in the faeces, giving an overall mean recovery of 94% administered radioactivity.

4. The predominant circulating components were identified as delafloxacin and a direct glucuronide conjugate of delafloxacin.     

Kinetics and disposition of picumeterol in animals

1. The pharmacokinetics and disposition of picumeterol, a novel β₂ receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels.

2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1?h in the rat and about 2?h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration.

3. Following instillation of ¹⁴C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2?min. After 2?h perfusion, no metabolites were detected in the recirculation perfusate or lung.

4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and β-oxidation are important as routes of metabolism.

5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.     

Pharmacokinetics of isoforskolin after administration via different routes in guinea pigs

1.?The objective of this study was to characterize the pharmacokinetics of isoforskolin after oral, intraperitoneal and intravenous administration, as well as to compare bioavailability.

2.?Isoforskolin was administered to guinea pigs at a dose of 2?mg/kg. Plasma concentrations were determined by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (HPLC–ESI–MS/MS) method. The pharmacokinetic parameters were calculated by a noncompartmental method. A compartment model was also adopted to describe the pharmacokinetic profiles.

3.?The pharmacokinetic behavior of intravenously administered isoforskolin was characterized by rapid and extensive distribution (V_z?=?16.82?±?8.42?L/kg) followed by rapid elimination from the body (Cl?=?9.63?±?4.21?L/kg/h). After intraperitoneal administration, isoforskolin was absorbed rapidly (T_max?=?0.12?±?0.05?h). The pharmacokinetic profiles of isoforskolin were similar after intraperitoneal and intravenous administration, except for the concentrations at the initial sampling times. Isoforskolin was also absorbed rapidly following oral dosing; however, the concentration–time data were best fit to a one-compartment model, which was different from that observed after intravenous and intraperitoneal administration. Following intraperitoneal and oral administration, the absolute bioavailability of isoforskolin was 64.12% and 49.25%, respectively.

4.?Isoforskolin is a good candidate for oral administration because of its good oral bioavailability.     

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.