Pharmacological and Pharmacokinetic Evaluation of EXP3312, an Orally-active Non-peptide Angiotensin II-Receptor Antagonist

EXP3312, 2-n-propyl-4-chloro-l-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylaldehyde, is a non-peptide angiotensin II (AII) AT₁-receptor antagonist. In the rabbit isolated aorta EXP3312 inhibited the contractile response to AII competitively with a pA₂ value of 8.24. In renal hypertensive rats EXP3312 reduced blood pressure with intravenous and oral ED30 values of 0.19 and 0.14 mg kg^?1, respectively. It also reduced blood pressure in frusemide-treated dogs when administered orally at 1 and 3 mg kg^?1. In rats and dogs, the absolute oral bioavailability of EXP3312 averaged 60 and 28%, respectively. When EXP3312 was administered intravenously to rats and dogs the plasma elimination half-lives were 1.20 and 2.52 h, respectively. In rats and dogs EXP3312 was metabolized to an active metabolite M1, 2-n-propyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. M1 is about ten times more potent than EXP3312 in renal hypertensive rats; the intravenous ED30 value was 0.02 mg kg^?1. Because high plasma levels of M1 were found in rats after oral administration of EXP3312, it is likely that M1 contributes to the long duration of the antihypertensive effects of EXP3312 in renal hypertensive rats. The results show that EXP3312 is a potent, orally active, competitive and selective AT₁-receptor antagonist and a potent antihypertensive agent; it is likely to be therapeutically useful in the treatment of hypertension and congestive heart failure.     

Identification of an N-Oxide as the Major Metabolite of the Analgesic O-(Diethylaminoethyl)-4-Chlorobenz-aldoxime Hydrochloride in Dogs

1. After oral administration to dogs of the analgesic O-(diethylaminoethyl)-4-chloro[7-¹⁴C]benzaldoxime hydrochloride together with piperazine hydro-chloride (2:1, w/w), at a dose of 4.5?mg/kg, the radioactivity was well absorbed and rapidly excreted. During 5 days, 81% of the dose (ca. 50% in 12?h) was excreted in urine and 10% in faeces.

2. Rates and routes of excretion of radioactivity were not altered in animals pre-treated with the drug for fourteen days.

3. Peak mean plasma concentrations of radioactivity (5.5 μg equiv./ml) occurred at 90 min after an oral dose and were higher than those at 2 min following an equivalent intravenous (3.4 μg equiv. /ml) or rectal (4.0 μg equiv. /ml) dose which gave a max. at 45?min.

4. The drug was rapidly and extensively metabolized and no unchanged drug was detected in the plasma or urine. The major urinary metabolite was the N-oxide of the parent compound accounting for 34% and 23% dose excreted in the urine of males and females respectively during 12?h after administration.     

Metabolism and disposition of a potent and selective JNK inhibitor [14C]tanzisertib following oral administration to rats,dogs and humans

Abstract

1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [¹⁴C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL).

2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (T_max: 1–2?h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas <34% was observed in rats. Variable amounts of unchanged tanzisertib (1.5–32% of dose) was recovered in urine/feces across all species, the highest in human feces.

3. Metabolic profiling revealed that tanzisertib was primarily metabolized via oxidation and conjugation pathways, but extensively metabolized in rats relative to dogs/humans. CC-418424 (S-cis isomer of tanzisertib) was the major plasma metabolite in rats (38.4–46.4% of plasma radioactivity), while the predominant plasma metabolite in humans and dogs was M18 (tanzisertib-/CC-418424 glucuronide), representing 7.7 and 3.2% of plasma radioactivity, respectively. Prevalent biliary metabolite in rats and dogs, M18 represented 16.8 and 17.1% of dose, respectively.

4. In vitro studies using liver subcellular fractions and expressed enzymes characterized involvement of novel human aldo-keto reductases for oxido-reduction and UDP-glucuronosyltransferases for conjugation pathways.     

Intestinal Transport of Gentamicin with a Novel,Glycosteroid Drug Transport Agent

Purpose. The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. Methods. Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. ³H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. Results. The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal or jejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. Conclusions. TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.     

Disposition and metabolic fate of prasugrel in mice,rats, and dogs

The disposition and metabolism of prasugrel, a thienopyridine prodrug and a potent inhibitor of platelet aggregation in vivo, were investigated in mice, rats, and dogs. Prasugrel was rapidly absorbed and extensively metabolized. In the mouse and dog, maximum plasma concentration of radioactivity was observed in less than 1?h after an oral [¹⁴C]prasugrel dose. Most of the administered prasugrel dose was recovered in the faeces of rats and dogs (72% and 52–73%, respectively), and in mice urine (54%). Prasugrel is hydrolysed by esterases to a thiolactone, which is subsequently metabolized to thiol-containing metabolites. The main circulating thiol-containing metabolite in the three animal species is the pharmacologically active metabolite, R-138727. The thiol-containing metabolites are further metabolized by S-methylation and conjugation with cysteine.     

Pharmacokinetics of carbamazepine polymorphs and dihydrate in rats,related to dogs and humans

Species differences in the oral pharmacokinetics and absolute bioavailability (F _abs ) of carbamazepine polymorphs (form I and form III) and dihydrate were studied. The pharmacokinetics of each form was investigated in rats following a single oral/intravenous administration of 10 mg/kg and an oral dose of 80 mg/kg, which were compared with the published data obtained from dogs and humans. No significant differences were found in their C _max, T _max, AUC_0−∞ and F _abs among the forms at the low dose. However, significant differences were observed at the high dose. The Fabs of each form was markedly reduced with increasing of doses in species (e.g. F _abs in rats ranged from > 82% to 38.4%–56.0%). At a comparable dose, the C _max, and AUC_0−∞ of rats and humans were about 3–10 times higher than in dogs. The absorption rate of form III in rats exhibited a similar trend to that in humans, and was far higher in dogs. A multi-peak phenomenon in plasma curves was observed in rats and humans, but not in dogs. In conclusion, rats appear to be a better predictor of carbamazepine polymorphs absorbed in humans, and form III may be more suitable as a pharmaceutical crystal.     

Mean Residence Time of Oral Drugs Undergoing First-Pass and Linear Reversible Metabolism

Equations for the mean residence times in the body (MRT) and AUMC/AUC of a drug and its metabolite have been derived for an oral drug undergoing first-pass and linear reversible metabolism. The mean residence times of the drug or interconversion metabolite in the body after oral drug are described by equations which include the mean absorption time (MAT), the mean residence times of the drug or metabolite in the body after intravenous administration of the drug, the fractions of the dose entering the systemic circulation as the parent drug and metabolite, and the systemically available fractions of the drug (F _p ^p) or metabolite (F _m ^p). Similarly, the AUMC/AUC of the drug and metabolite after oral drug can be related to the MAT, ratios of the fraction of the dose entering the systemic circulation to the systemically available fraction, the first-time fractional conversion of each compound, and AUMC/AUC ratios after separate intravenous administration of each compound. The F _p ^p and F _m ^p values, in turn, are related to the first-pass availabilities of both drug and metabolite and the first-time fractional conversion fractions. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.     

Primary,secondary, and tertiary metabolite kinetics

Because of the propensity of nascently formed metabolites towards sequential metabolism within formation organs, theoretical and experimental treatments that achieve mass conservation must recognize the various sources contributing to primary, secondary, and tertiary metabolite formation. A simple one-compartment open model, with first-order conditions and the liver as the only organ of drug disappearance and metabolite formation, was used to illustrate the metabolism of a drug to its primary, secondary, and tertiary metabolites, encompassing the cascading effects of sequential metabolism. The concentration-time profiles of the drug and metabolites were examined for two routes of drug administration, oral and intravenous. Formation of the primary metabolite from drug in the gut lumen, with or without further absorption, and metabolite formation arising from first-pass metabolism of the drug and the primary metabolite during oral absorption were considered. Mass balance equations, incorporating modifications of the various absorption and conversion rate constants, were integrated to provide the explicit solutions. Simulations, with and without consideration of the sources of metabolite formation other than from its immediate precursor, were used to illustrate the expected differences in circulating metabolite concentrations. However, a simple relationship between the area under the curve of any metabolite, M,or [AUC{m}],its clearance [CL{m}],and route of drug administration was found. The drug dose, route, fraction absorbed into the portal circulation, F_abc,fraction available of drug from the liver, F,availabilities of the metabolites F{m}from formation organs, and CL{m}are determinants of the AUC{m}'s.After iv drug dosing, the area of any intermediary metabolites is determined by the iv drug dose divided by the (CL{m}/F{m})of that metabolite. When a terminal metabolite is not metabolized,its area under the curve becomes the iv dose of drug divided by the clearance of the terminal metabolite since the available fraction for this metabolite is unity. Similarly, after oral drug administration, when loss of drug in the gut lumen does not contribute to the appearance of metabolites systemically, the general solution for AUC{m} isthe product of F_abc and oral drug dose divided by [CL{m}/F{m}].A comparison of the area ratios of any metabolite after po and iv drug dosing, therefore, furnishes F_abc.When this fraction is divided into the overall systemic availability or F_sys,the drug availability from the first-pass organs, F,may be found. The potential application of these relationships to other schemes, namely, drugs that have competing metabolic pathways within the liver and/or intestine as well as reversible metabolism is briefly discussed.In view of the various contributing sources of metabolite formation, and the modulation of circulating metabolite concentrations by sequential first-pass metabolism of the metabolite, caution is given against the use of area ratios of metabolite after iv drug and metabolite administration for estimations of metabolite formation clearances.This work was supported by the Medical Research Council of Canada (MA-9104 and MA-9765) and the NIH (GM-38250). KSP is a recipient of the Faculty Development Award from MRC, Canada.     

Pharmacokinetics of Ketorolac and p-Hydroxyketorolac Following Oral and Intramuscular Administration of Ketorolac Tromethamine

Ketorolac tromethamine (KT), a potent analgesic with cyclooxygenase inhibitory activity, was administered in an open, randomized, single-dose study of Latin-square design to 12 healthy male volunteers. Doses of 30 mg oral (po) and 30, 60, and 90 mg intramuscular (im) KT were administered in solution. Plasma samples were analyzed for ketorolac (K) and its inactive metabolite, p-hydroxyketorolac (PHK), by reversed-phase high-performance liquid chromatography (HPLC). The 30-mg im dose was found to be similar to the 30-mg po dose with respect to total AUC values for both K and PHK. The amount of PHK circulating in plasma was very low as judged by AUC ratios (PHK/K × 100) of 1.9 and 1.5% for the 30-mg po and im doses, respectively. The rate of absorption of K and formation of PHK, as determined by C _max and T _max values, was significantly slower following the im doses. Total AUC and C _max for K and PHK increased linearly with dose after im administration of 30, 60, and 90 mg of KT. The mean plasma half-life of K was remarkably consistent between po and im administration and was independent of dose, ranging from 5.21 to 5.56 hr. The plasma metabolic profile was similar following both routes of administration and graded im doses.     

Disposition and metabolism of TAK-438 (vonoprazan fumarate), a novel potassium-competitive acid blocker,in rats and dogs

1.?Following oral administration of [¹⁴C]TAK-438, the radioactivity was rapidly absorbed in rats and dogs. The apparent absorption of the radioactivity was high in both species.

2.?After oral administration of [¹⁴C]TAK-438 to rats, the radioactivity in most tissues reached the maximum at 1-hour post-dose. By 168-hour post-dose, the concentrations of the radioactivity were at very low levels in nearly all the tissues. In addition, TAK-438F was the major component in the stomach, whereas TAK-438F was the minor component in the plasma and other tissues. High accumulation of TAK-438F in the stomach was observed after oral and intravenous administration.

3.?TAK-438F was a minor component in the plasma and excreta in both species. Its oxidative metabolite (M-I) and the glucuronide of a secondary metabolite formed by non-oxidative metabolism of M-I (M-II-G) were the major components in the rat and dog plasma, respectively. The glucuronide of M-I (M-I-G) and M-II-G were the major components in the rat bile and dog urine, respectively, and most components in feces were other unidentified metabolites.

4.?The administered radioactive dose was almost completely recovered. The major route of excretion of the drug-derived radioactivity was via the feces in rats and urine in dogs.     

Lisdexamfetamine and amphetamine pharmacokinetics in oral fluid,plasma, and urine after controlled oral administration of lisdexamfetamine

Lisdexamfetamine (LDX) is a long‐acting prodrug stimulant indicated for the treatment of attention‐deficit/hyperactivity disorder (ADHD) and binge‐eating disorder (BED) symptoms. In vivo hydrolysis of the LDX amide bond releases the therapeutically active d‐amphetamine (d‐AMPH). This study aims to describe the pharmacokinetics of LDX and its major metabolite d‐AMPH in human oral fluid, urine and plasma after a single 70 mg oral dose of LDX dimesylate. Six volunteers participated in the study. Oral fluid and blood samples were collected for up to 72 h and urine for up to 120 h post‐drug administration for the pharmacokinetic evaluation of intact LDX and d‐AMPH. Samples were analyzed by LC‐MS/MS. Regarding noncompartmental analysis, d‐AMPH reached the maximum concentration at 3.8 and 4 h post‐administration in plasma and oral fluid, respectively, with a mean peak concentration value almost six‐fold higher in oral fluid. LDX reached maximum concentration at 1.2 and 1.8 h post‐administration in plasma and oral fluid, respectively, with a mean peak concentration value almost three‐fold higher in plasma. Intact LDX and d‐AMPH were detected in the three matrices. The best fit of compartmental analysis was found in the one‐compartment model for both analytes in plasma and oral fluid. There was a correlation between oral fluid and plasma d‐AMPH concentrations and between parent to metabolite concentration ratios over time in plasma as well as in oral fluid.     

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 a non-narcotic analgesic,DA-5018, in rats

The pharmacokinetics of a non-narcotic analgesic, DA-5018, were compared after single intravenous (IV), subcutaneous (SC), and oral administrations, and after multiple (seven consecutive days) SC administration to rats. After IV administration of DA-5018, 1, 2, and 5 mg kg⁻¹, the pharmacokinetic parameters of DA-5018 were independent of the dose ranges studied. After oral administration of DA-5018, absorption of the drug from gastrointestinal (GI) tract was fast, but the extent of absolute bioavailability (F) was low; the values were 23.2, 23.0, and 27.3% for 2, 5, and 10 mg kg⁻¹, respectively. After single SC administration of DA-5018, absorption of the drug from the injected site was fast and the extent of absorption was fairly good; the F values were 74.5 and 71.8% for 2 and 5 mg kg⁻¹, respectively. The lower F values after oral administration of DA-5018 to rats could be due to degradation of the drug in rat GI tract and/or considerable first-pass effect. After IV, oral, and SC administration of DA-5018, the drug had a strong affinity to the rat tissues studied as reflected in the greater-than-unity tissue to plasma ratio. After IV, oral, and SC administration of the drug, the biliary and urinary excretion of unchanged DA-5018 were negligible. There was no significant difference in the pharmacokinetics or tissue distribution of DA-5018 between single and multiple SC administration of the drug, 5 mg kg⁻¹, to rats, indicating that there could be no tissue accumulation of the drug after multiple SC administration of the drug to rats. © 1998 John Wiley & Sons, Ltd.     

Disposition of a new tetrahydrocarbazole analgesic drug in laboratory animals and man

1. The disposition of AY-30,068 (I), a new tetrahydrocarbazole analgesic drug, was studied in mice, rats, dogs, rhesus monkeys, and man.

2. Oral doses of the ¹⁴C-labelled drug in aqueous solution were well absorbed in rodents, but absorption of oral doses of the crystalline drug in dogs was poor. Due to the virtual absence of serum metabolites in rats and dogs, the bioavailability of I was nearly identical to the extent of absorption. Although a small first-pass effect was observed in mice, unchanged I represented a major portion of serum radioactivity.

3. A linear increase in the serum concentrations of I occurred at doses between 0.05 and 25?mg/kg in rats, 0.1 and 50?mg/kg in dogs, and 1–160?mg in man. In rhesus monkeys given a 0.5?mg/kg oral dose, the C_max and AUC of I were similar to values obtained following a corresponding dose in dogs.

4. After i.v. administration of a 1.0?mg/kg dose the terminal elimination half-life (t1/2β) of I was 4?h in mice and 9–10h in rats and dogs. In rodents, dogs, and several human subjects, the elimination of I was interrupted by secondary peaks. Enterohepatic circulation was confirmed in bile duct cannulated rats, where the t1/2β of I was decreased to 2.4?h. In rodents the serum clearance and apparent volume of distribution of I were 0.04–0.21/kg.?h and 0.5–0.81/kg, respectively, and 0.61/kg.h and 9.81/kg in dogs.

5. In rodents and dogs dosed with ¹⁴C-labelled I, radioactivity was excreted almost entirely in the faeces. No unchanged I was detected in rat bile, while about 70% of the radioactivity corresponded to conjugates of parent drug.     

Absorption,metabolism and excretion of cobimetinib,an oral MEK inhibitor,in rats and dogs

1.?The absorption, metabolism and excretion of cobimetinib, an allosteric inhibitor of MEK1/2, was characterized in mass balance studies following single oral administration of radiolabeled (¹⁴C) cobimetinib to Sprague–Dawley rats (30?mg/kg) and Beagle dogs (5?mg/kg).

2.?The oral dose of cobimetinib was well absorbed (81% and 71% in rats and dogs, respectively). The maximal plasma concentrations for cobimetinib and total radioactivity were reached at 2–3?h post-dose. Drug-derived radioactivity was fully recovered (～90% of the administered dose) with the majority eliminated in feces via biliary excretion (78% of the dose for rats and 65% for dogs). The recoveries were nearly complete after the first 48?h following dosing.

3.?The metabolic profiles indicated extensive metabolism of cobimetinib prior to its elimination. For rats, the predominant metabolic pathway was hydroxylation at the aromatic core. Lower exposures for cobimetinib and total radioactivity were observed in male rats compared with female rats, which was consistent to in vitro higher clearance of cobimetinib for male rats. For dogs, sequential oxidative reactions occurred at the aliphatic portion of the molecule. Though rat metabolism was well-predicted in vitro with liver microsomes, dog metabolism was not.

4.?Rats and dogs were exposed to the two major human circulating Phase II metabolites, which provided relevant metabolite safety assessment. In general, the extensive sequential oxidative metabolism in dogs, and not the aromatic hydroxylation in rats, was more indicative of the metabolism of cobimetinib in humans.     

Chlorpheniramine. II. Effect of the first-pass metabolism on the oral bioavailability in dogs

The pharmacokinetics of chlorpheniramine has been studied in six dogs by following the time course of plasma concentration of the drug after intravenous and oral administration of its maleate salt in solution form. After intravenous dosing the decline in chlorpheniramine plasma concentration was typically biexponential. The drug distributed rapidly and extensively to the extravascular tissues. The mean distribution phase halflife was 12.5 min, and the mean apparent volume of distribution, Vd, was 525% ofthe body weight in four dogs with normal hematocrits. The mean half-life of elimination was 1.7hr. The percent absolute availability following oral administration of the drug in the aqueous solution form was found to be dose dependent. At 100-mg dose, in six dogs, an average of 36% of the orally administered dose was found to be systemically available. At 50-mg dose, in one of the four dogs studied, no measurable plasma levels of chlorpheniramine were obtained, and the average bioavailability was only 9.4%. The average availability in four dogs at 200-mg dose was 39.4%. Even at 200-mg oral dose, the dogs did not show any signs of sedation and remained alert all through the experiment. Saturable first-pass gut and/or hepatic elimination has been postulated. The possible implications of these findings on the therapeutic effectiveness of the usual dosing regimen of chlorpheniramine in dogs are discussed.     

Toxicokinetics of methyl paraoxon in the dog

The toxicokinetics of methyl paraoxon, the active metabolite of the organophosphorus insecticide methyl parathion, were studied in non-anaesthetized dogs after intravenous (2.5 mg/kg) and oral (15 mg/kg) administration of methyl paraoxon. After intravenous administration, distribution and elimination occured very rapidly and using the data from 5 min post-injection, the plasma concentration versus time curves could be fitted to a one-compartment open model. The mean half-life of elimination was 9.7 min, the average volume of distribution 1.76 l/kg and the average plasma clearance 126 ml/kg/min. After oral administration, peak plasma concentrations were obtained within 3–16 min, and the bioavailability varied from 5 to 71%. The hepatic extraction of methyl paraoxon measured in anaesthetized dogs, was high (70–92%). Comparison of the urinary excretion after intravenous and oral administration in two dogs indicated a gastrointestinal absorption of more than 60%. The kinetics of methyl paraoxon were linear in the dose range tested.     

Comparison of formation of thiolactones and active metabolites of prasugrel and clopidogrel in rats and dogs

1. Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites.

2. The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg^?1) and clopidogrel (0.77 mg kg^?1) were 15.8 ± 15.9 ng h ml^?1 and 0.113 ± 0.226 ng h ml^?1, respectively, in rats, and 454 ± 104 ng h ml^?1 and 23.3 ± 4.3 ng h ml^?1, respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine.

3. The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs.

4. Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process.

5. In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel’s thiolactone and active metabolite.

     

Pharmacokinetic characterization of ginsenoside Rh2, an anticancer nutrient from ginseng, in rats and dogs

The pharmacokinetic characteristics of ginsenoside Rh2, an anticancer nutrient, were analyzed in dogs and rats, including plasma kinetics, bioavailability, tissue distribution, plasma protein binding and excretion. The bioavailability of Rh2 is about 5% in rats and 16% in dogs. Multiple-dosing (7 days, 1 mg/kg bid) did not affect the pharmacokinetics in dogs. After oral dosing, Rh2 distributed mainly to the liver and gastrointestinal tissues in rats. In rats, the circulating fraction of Rh2 bound to plasma proteins was around 70%. The systemic clearance, however, was low – around 2 and 20 ml/min/kg in dogs and rats, respectively. Only 1% of dosed Rh2 were recovered in excreta of rats as the intact form after oral administration, while 30% was excreted unchanged in bile after i.v. dosing. We subsequently investigated the membrane permeability of Rh2 across Caco-2 cell monolayers, stability and elimination profiles in the gastrointestinal environment. Low membrane permeability (P_app(AP − BL): 1.91 × 10⁻⁸ cm/s), efflux transport (efflux ratio: 9.8), pre-systemic elimination (degradation in acidic condition; metabolism in intestine tissue and contents), as well as low solubility largely accounted for the low bioavailability of Rh2. Regarding the low solubility of Rh2, micronization of the dose almost doubled the rate of absorption in dogs. Preliminary metabolite profiling confirmed the presence of the deglycosidating product protopanaxadiol in rat feces. A possible metabolite in rat bile and a potential sulfate-conjugate in rat urine were also detected.     

Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 +/- 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 +/- 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were approximately 20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.