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, (14)C-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-infinity) of total radioactivity were 36.2 and 47.1 microg eqx 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.     

Absorption,distribution, metabolism and excretion of loxoprofen after dermal application of loxoprofen gel to rats

Abstract

1. Loxoprofen (LX), is a prodrug of the pharmacologically active form, trans-alcohol metabolite (trans-OH form), which shows very potent analgesic effect. In this study, the pharmacokinetics and metabolism of [¹⁴C]LX-derived radioactivity after dermal application of [¹⁴C]LX gel (LX-G) to rats were evaluated.

2. The area under concentration-time curve (AUC_0–∞) of radioactivity in the plasma after the dermal application was 13.6% of that of the oral administration (p?<?0.05).

3. After the dermal application, the radioactivity remained in the skin and skeletal muscle at the treated site for 168?h, whereas the AUC_0–168?h of the radioactivity concentration in every tissue examined except the treated site was statistically lower than that after the oral administration (p?<?0.05).

4. The trans-OH form was observed at high levels in the treated skin site at 0.5?h. Metabolite profiles in plasma, non-treated skin site and urine after the dermal application were comparable with those after the oral administration.

5. Renal excretion was the main route of elimination after the dermal application.

6. In conclusion, compared to the oral administration, the dermal application of [¹⁴C]LX-G showed lower systemic and tissue exposure with higher exposure in the therapeutic target site. The radioactivity revealed similar metabolite profiles in both administration routes.     

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.     

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.     

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.     

Oral absorption,metabolism and excretion of 1-phenoxy-2-propanol in rats

1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers.

2. Rats were administered a single oral dose of 10 or 100?mg?kg^{?1 14}C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0–12, 12–24 and 24–48?h and faeces at 0–24 and 24–48?h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS.

3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 ± 5% of the low and 96 ± 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12?h after dosing; 85 ± 2% of the low and 90 ± 1% of the high dose. Total faecal excretion remained 4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.     

Metabolism,excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration

1.?The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100?mg/100 μCi [¹⁴C]glasdegib to six healthy male volunteers (NCT02110342).

2.?The peak concentrations of glasdegib (890.3?ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75?hours post-dose. The AUC_inf were 8469?ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity.

3.?Mean recovery of [¹⁴C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0–120?hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites.

4.?Elimination of [¹⁴C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.     

The metabolism and pharmacokinetics of [14C]-S-777469, a new cannabinoid receptor 2 selective agonist,in healthy human subjects

Abstract

1.?The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration of [¹⁴C]-S-777469 to healthy human subjects.

2.?Total radioactivity was rapidly and well absorbed in humans, with C_max of 11?308?ng eq. of S-777469/ml at 4.0?h. The AUC_inf ratio of unchanged S-777469 to total radioactivity was approximately 30%, indicating that S-777469 was extensively metabolized in humans.

3.?The metabolite profiling in human plasma showed that S-777469 5-carboxymethyl (5-CA) and S-777469 5-hydroxymethyl (5-HM) were the main circulating metabolites, and the AUC_inf ratio of 5-CA and 5-HM to total radioactivity were 24 and 9.1%, respectively. These data suggest that S-777469 was subsequently metabolized to 5-CA in humans although the production amount of 5-CA was extremely low in human hepatocytes.

4.?Total radioactivity was mainly excreted via the feces, with 5-CA and 5-HM being the main excretory metabolites in feces and urine. Urinary excretion of 5-CA was comparable with that of 5-HM, whereas fecal excretion of 5-CA was lower than that of 5-HM.

5.?In conclusion, the current mass balance study revealed the metabolic and pharmacokinetic properties of S-777469 in humans. These data should be useful to judge whether or not the safety testing of metabolite of S-777469 is necessary.     

Localization and disposition of a non-peptide angiotensin II type 1 receptor antagonist,and its glucuronide metabolite,in rat

1. The disposition of radioactivity of a non-peptide angiotensin II type 1 receptor antagonist (E4177) has been studied in groups of male rats after a single oral 1?mg/kg dose of ¹⁴C-E4177 was administered by gavage. We have also used light-microscopic autoradiography to investigate the localization of radioactivity in the target tissues for this angiotensin II receptor antagonist. 2. The radioactivity was absorbed quickly, and the maximum blood levels (C_max) were reached at 0·38 ± 0·14?h after dosing. The concentrations then declined bi-exponentially with a mean apparent half-life for the first phase (t_½α) of 0·46 ± 0·07?h and a terminal half life (t_½β) of 6·22 ± 1·08?h. By 24 h, the levels had decreased to 2·7 ± 1·5% C_max. The blood beta max levels radioactivity at 48?h after administration were below the limit of quantification. 3. Radioactivity was distributed throughout the body at 15?min after administration. Tissues inwhich radioactivity was present at higher levels thaninplasma were the liver and kidney. Radioactivity was rapidly eliminated from the tissues and was not retained in any individual organ. 4. The major route of excretion was via the bile. Since > 90% of the administered radioactivity was recovered by 24?h after administration, the excretion was relatively rapid. The major metabolite in bile was a glucuronide of E4177 biphenylcarboxylic acid (E4177- Glu). 5. Light-microscopic autoradiographic observations revealed a strong localization of radioactivity throughout the surface cells of the adrenal glomerulosa, the blood vessels in kidney and the surface of the aortic smooth muscle cells, which are all rich in angiotensin II type 1 (AT1) receptors.     

Pharmacokinetics of single oral and multiple intravenous and oral administration of acebutolol enantiomers in a rat model

Acebutolol (AC), is a chiral, β -adrenergic blocking agent which possesses partial agonist activity and is metabolized to an equipotent chiral metabolite, diacetolol (DC). The enantiomeric disposition of AC is reported following racemic administration as a single oral (p.o., 50 mg kg⁻¹) or as a multiple thrice daily intravenous (i.v.) or p.o. dosing for four days in male Sprague–Dawley rats (n =6). Enantiomeric concentrations of AC and DC in plasma and urine were determined using a stereospecific HPLC assay. The bioavailabilities of R- and S-enantiomer were 0.40 and 0.39 after single dose administration of AC respectively. These values were increased to 0.51 and 0.53 after multiple dosing. Although no significant differences were found in AUC_0–∞ after single i.v. as compared with AUC_0–τ after multiple i.v. dosing of AC, the 39 and 45% increase in mean AUC_0–τ were found after multiple p.o. dosing over the corresponding AUC_0–∞, for the single p.o. dose of AC for R- and S-enantiomer, respectively. The disposition of DC as well as the urinary excretion of metabolite was stereoselective in favor of R-enantiomer after oral administration of AC. These results indicate that AC enantiomers have low availability and moderate extraction through the first-pass metabolism in a rat model. The higher AUC values after p.o. multiple dosing may suggest a saturable first-pass metabolism of AC. © 1998 John Wiley & Sons, Ltd.     

Metabolism,pharmacokinetics and excretion of a potent tachykinin NK1 receptor antagonist (CP-122,721) in rat: Characterization of a novel oxidative pathway

The metabolism, pharmacokinetics and excretion of a potent and selective substance P receptor antagonist, (+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzlamino)-2-phenylpiperidine, CP-122,721, have been studied in rat following oral administration of a single dose of [¹⁴C]CP-122,721. Total recovery of the administered dose was 84.1?±?1.1% for male rat and 80.9?±?2.7% for female rat. Approximately 81% of the administered radioactivity recovered in urine and faeces were excreted in the first 72?h. Absorption of CP-122,721 was rapid in both male and female rat, as indicated by the rapid appearance of radioactivity in plasma. The plasma concentrations of total radioactivity were always much greater than unchanged drug, indicating early formation of metabolites. CP-122,721 t_1/2 was 3.1 and 2.2?h for male and female rat, respectively. The plasma concentrations of CP-122,721 reached a peak of 941 and 476?ng?ml^?1 for male and female rat, respectively, at 0.5?h post-dose. Based on AUC_0–tlast, only 1.5% of the circulating radioactivity was attributable to unchanged drug (average of male and female rats) and the balance, approximately 98.5% of the plasma radioactivity was due to metabolites. The major metabolic pathways of CP-122,721 were due to O-demethylation, aromatic hydroxylation and indirect glucuronidation. The minor metabolic pathways included aliphatic oxidation at the piperidine moiety and aliphatic oxidation at the benzylic position of the trifluoromethoxy anisole moiety. In addition, a novel oxidative metabolite resulting from ipso substitution by the oxygen atom and trifluoromethoxy elimination followed by glucuronide conjugation was also identified.     

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.

     

Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition

DMXBA (3-(2, 4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg⁻¹ iv dose, DMXBA plasma concentration declined bi-exponentially with mean (±SE) absorption and elimination half-lives of 0.71±0.28 and 3.71±1.12 h, respectively. The apparent steady state volume of distribution was 2150±433 mL kg⁻¹, total body clearance was 1480±273 mL h⁻¹ kg⁻¹, and AUC_0–∞ was 3790±630 ng h mL⁻¹. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg⁻¹, a peak plasma concentration of 1010±212 ng mL⁻¹ was observed at 10 min after dosing. Elimination half-life was 1.740±0.34 h, and AUC_0–∞ was 1440±358 ng h mL⁻¹. DMXBA peak brain concentration after oral administration was 664±103 ng g⁻¹ tissue, with an essentially constant brain–plasma concentration ratio of 2.61±0.34, which indicates that the drug readily passes across the blood–brain barrier. Serum protein binding was 80.3±1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h⁻¹ kg⁻¹) was less than 2% of the total clearance (1480±273 mL h⁻¹ kg⁻¹); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28±0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism. © 1998 John Wiley & Sons, Ltd.     

Absorption,metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog

1. The oral no overall adverse effect level (NOAEL) for chronic toxicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat is ~1.3?mg kg^-1 and in dog is 0.2 mgkg^-1. In an attempt to explain the difference in toxicology between these species, rats and dogs were orally dosed with (¹⁴C)-MCPA at 5 or 100?mg kg^-1 and plasma toxicokinetics, rates and routes of excretion and biotransformation were investigated. 2. Elimination of radioactivity in rat plasma was biphasic and in dog was monophasic. Rat eliminated radioactivity from plasma significantly faster than dog (approximate values based on total radioactivity: 5 mgkg^-1 rat: t_½dist 3.5 h, t_½elim 17.2-36.2 h, AUC_(0-∞) 230 µg equiv h g^-1; 5 mgkg^-1 dog: t_½47 h, AUC_(0-∞) 2500 µg equiv h g^-1; 100mg kg^-1 rat: t_½dist 10 h, t_½elim 10.27-25.4 h, AUC_(0-∞) 5400 µg equiv h g^-1; 100?mg kg^-1 dog: t_½41 h, AUC_(0-∞) 20 500µg equiv h g^-1). 3. For both species, the principal route of excretion was in urine but renal elimination was notably more rapid and more extensive in rat. 4. In both rat and dog, excretion of radioactivity was mainly as MCPA and its hydroxylated metabolite hydroxymethylphenoxyacetic acid (HMCPA). In rat, both were mainly excreted as the free acids although a small proportion was conjugated. In dog, the proportion of HMCPA was increased and the majority of both species was excreted as glycine or taurine conjugates. 5. These data, along with previously published accounts, indicate that renal elimination of MCPA in dog is substantially slower than in rat resulting in disproportionate elevation of AUC (based on total radioactivity) in dog compared with rat.     

Pharmacokinetics,metabolism and excretion of an inhibitor of inducible nitric oxide synthase,L-NIL-TA,in dog

1.?The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog.

2.?The dose of [¹⁴C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5?mg?kg^?1), with C_max of radioactivity of 6.45–7.07?μg equivalents?g^?1 occurring at 0.33–0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively.

3.?Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [¹⁴C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%.

4.?Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.     

Sex differences in the metabolism and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1?mg/kg of the ¹⁴C-labelled compound.

2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48?h were 8.41% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces.

3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with ¹⁴C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats.

4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24?h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Absorption,distribution, metabolism and excretion of telmesteine,amucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of ¹⁴C-telmesteine in the Sprague–Dawley rat.

2. ¹⁴C-telmesteine was rapidly absorbed after oral dosing (20 and 50mg kg^-1) with an oral bioavailability of > 90% both in male and female rats. The C_max and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats.

3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30min after dosing was relatively low with a range of 0.1–0.8 except for excretory organs.

4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma.

5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Human mass balance,pharmacokinetics and metabolism of rovatirelin and identification of its metabolic enzymes in vitro

Abstract

1. The mass balance, pharmacokinetics and metabolism of rovatirelin were characterised in healthy male subjects after a single oral dose of [¹⁴C]rovatirelin. [¹⁴C]Rovatirelin was steadily absorbed, and the peak concentrations of radioactivity and rovatirelin were observed in plasma at 5–6?h after administration. The AUC_inf of radioactivity was 4.9-fold greater than that of rovatirelin. Rovatirelin and its metabolite (thiazoylalanyl)methylpyrrolidine (TAMP) circulated in plasma as the major components. The total radioactivity recovered in urine and faeces was 89.0% of the administered dose. The principal route of elimination was excretion into faeces (50.1% of the dose), and urinary excretion was the secondary route (36.8%). Rovatirelin was extensively metabolised to 20 metabolites, and TAMP was identified as the major metabolite in plasma and excreta among its metabolites.

2. To identify the metabolic enzymes responsible for TAMP formation, the in vitro activity was determined in human liver microsomes. The enzymatic activity depended on NADPH, and it was inhibited by ketoconazole. Furthermore, recombinant human cytochrome P450 (CYP) 3A4 and CYP3A5 displayed enzymatic activity in the assay. Therefore, CYP3A4/5 are the most important enzymes responsible for TAMP formation.

     

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.     

Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog

We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog.

2. Unavailability of YM17E was 5–9% at oral doses of 3–30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30mg/kg in dog.

3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with (hat of unchanged drug.

4. When ¹⁴C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation.

5. After oral administration of ¹⁴C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration.

6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA: cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites.

7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism.

8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of ¹⁴C-YM17E.