Clinical disposition,metabolism and in vitro drug–drug interaction properties of omadacycline

1.?Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects.

2.?Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters.

3.?Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300?mg oral dose of [¹⁴C]-omadacycline (36.6 μCi). Absorption was rapid with peak radioactivity (～610 ngEq/mL) between 1–4?h in plasma or blood. The AUC_last of plasma radioactivity (only quantifiable to 8?h due to low radioactivity) was 3096 ngEq?h/mL and apparent terminal half-life was 11.1?h. Unchanged omadacycline reached peak plasma concentrations (～563?ng/mL) between 1–4?h. Apparent plasma half-life was 17.6?h with biphasic elimination. Plasma exposure (AUC_inf) averaged 9418?ng?h/mL, with high clearance (CL/F, 32.8?L/h) and volume of distribution (Vz/F 828?L). No plasma metabolites were observed.

4.?Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.     

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.     

Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand,in healthy volunteers

1.?This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of ¹⁴C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease.

2.?Six healthy male subjects received a single oral dose of tozadenant (240?mg containing 81.47?KBq of [¹⁴C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection.

3.?At 4?h, the C_max of tozadenant was 1.74?μg/mL and AUC_(0–t) 35.0?h?μg/mL, t_1/2 15?h, Vz/F 1.82?L/kg and CL/F 1.40?mL/min/kg. For total [¹⁴C] radioactivity, the C_max was 2.29?μg?eq/mL at 5?h post-dose and AUC_(0–t) 43.9?h?μg?eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC_(0–48h). At 312?h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites.

4.?The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.     

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.     

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.     

A conscious rat model involving bradycardia and hypotension after oral administration: a toxicokinetical study of aconitine

1.?A model of aconitine-induced bradycardia and hypotension, which is similar to aconitine poisoning in humans, was constructed in conscious rats by oral administration.

2.?Blood pressure (BP) and heart rate (HR) of Sprague-Dawley rats were measured using a volume pressure recording (VPR) system. The pharmacokinetics of toxic doses of aconitine and its metabolites were analyzed using UPLC-MS/MS.

3.?The HR was significantly decreased by 29% at 2?h after oral administration of 200?μg/kg aconitine. When the dose was increased to 400?μg/kg, systolic BP and diastolic BP were significantly decreased by 11% and 12% at 2?h after the administration, except when bradycardia occurred at 2?h and 4?h. The drug concentration-time curve showed a double-peak phenomenon in rats administered a 400?μg/kg dose. The AUC_0–12?h value in the 400?μg/kg group significantly increased 0.8-fold compared to the 200?μg/kg group. Moreover, a high plasma concentration of 16-O-demethyaconitine was found in the rats that received two toxic doses.

4.?In conclusion, bradycardia and hypotension are induced in conscious rats by a toxic dose of aconitine (400?μg/kg), and there was no significant difference in dose-normalized AUC_0–12?h values between oral administrations of 200?μg/kg and that of 400?μg/kg. However, the dose-normalized C_max and AUC_0–12?h values in 200?μg/kg and 400?μg/kg groups were significantly smaller than those in 100?μg/kg group. The metabolites of aconitine, 16-O-demethyaconitine, and benzoylaconitine may also contribute to the hypotensive response.     

Lumiracoxib metabolism in male C57bl/6J mice: characterisation of novel in vivo metabolites

1.?The pharmacokinetics and metabolism of lumiracoxib in male C57bl/6J mice were investigated following a single oral dose of 10?mg/kg.

2.?Lumiracoxib achieved peak observed concentrations in the blood of 1.26?+?0.51?μg/mL 0.5?h (0.5–1.0) post-dose with an AUC_inf of 3.48?+?1.09?μg?h/mL. Concentrations of lumiracoxib then declined with a terminal half-life of 1.54?+?0.31?h.

3.?Metabolic profiling showed only the presence of unchanged lumiracoxib in blood by 24?h, while urine, bile and faecal extracts contained, in addition to the unchanged parent drug, large amounts of hydroxylated and conjugated metabolites.

4.?No evidence was obtained in the mouse for the production of the downstream products of glutathione conjugation such as mercapturates, suggesting that the metabolism of the drug via quinone–imine generating pathways is not a major route of biotransformation in this species. Acyl glucuronidation appeared absent or a very minor route.

5.?While there was significant overlap with reported human metabolites, a number of unique mouse metabolites were detected, particularly taurine conjugates of lumiracoxib and its oxidative metabolites.     

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.     

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 tafamidis,a transthyretin amyloidosis drug,in rats

1.?We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3–3?mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined.

2.?After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (V_ss) and half-life (T_½) remained unaltered as a function of dose, with values in the ranges of 6.41–7.03?mL/h/kg, 270–354?mL/kg and 39.5–46.9?h, respectively. Following oral administration, absolute bioavailability was 99.7–104% and was independent of doses from 0.3 to 3?mg/kg. In the urine and faeces, 4.36% and 48.9% of tafamidis, respectively, were recovered.

3.?Tafamidis was distributed primarily in the liver and not in the brain, kidney, testis, heart, spleen, lung, gut, muscle, or adipose tissue. Further, tafamidis was very stable in rat liver microsomes, and its plasma protein binding was 99.9%.

4.?In conclusion, tafamidis showed dose-independent pharmacokinetics with intravenous and oral doses of 0.3–3?mg/kg. Tafamidis undergoes minimal first-pass metabolism, distributes mostly in the liver and plasma, and appears to be eliminated primarily via biliary excretion.     

Effect of inhalation exposure to toluene on the activity of organic anion transporting polypeptide (Oatp) using pravastatin as a probe drug in rats

1.?Toluene, used as a pure substance or in solvent mixtures, is the cause of occupational exposures of large numbers of workers in the world. The organic anion transporting polypeptides (OATP: human; Oatp: rodents) are drug carriers which have been frequently associated to drug–drug interactions. The objective of this study was to evaluate the influence of inhalation exposure to toluene in Oatp in vivo activity using pravastatin as a probe drug in rats.

2.?Male Wistar rats ((n?=?6 per sampling time) were exposed to 85 mg/m³ toluene by inhalation or air in a nose only exposure system for 6 h/d, 5 d/week during 4 weeks, in order to simulate the occupational exposure to toluene at level slightly above the occupational exposure limit proposed by the American Conference of Governmental Industrial Hygienists (ACGIH). After 4 weeks of exposure, animals received a single dose of 20 mg/kg pravastatin orally.

3.?Areas under concentration × time curves extrapolated to infinite (AUC^0–∞) were calculated by Gauss Laguerre quadrature. Non-exposed animals showed AUC^0–∞ of 726.0 (261.8) ng h/mL for pravastatin and rats exposed to toluene 85 mg/m3 showed AUC^0–∞ of 681.8 (80.1)?ng?h/mL [data presented as mean (standard error of the mean)]. No significant difference was observed in pravastatin kinetic disposition between groups in terms of 95% confidence interval for the difference between means.

4.?Toluene exposure by inhalation did not change the in vivo activity of Oatp evaluated by pravastatin kinetic disposition in rats.     

Pharmacokinetics,pharmacokinetic–pharmacodynamic relationship,and withdrawal period of amoxicillin sodium in olive flounder (Paralichthys olivaceus)

1.?The pharmacokinetics (PK) and withdrawal period of amoxicillin sodium in olive flounder and its activity against pathogenic bacteria of olive flounder were investigated.

2.?Intramuscular administration (12.5 or 125?mg/kg, n?=?160) and HPLC analysis of sera were used.

3.?Rapid absorption (T_max 2.6 and 2.2?h), prolonged action (terminal half-life, 15.52 and 10.42?h; MRT, 18.79 and 14.44?h), and dose-proportional exposure (AUC_0–∞, 273.69 and 2755.37?h. μg/ml) were observed after 12.5 and 125?mg/kg doses.

4.?The withdrawal period of amoxicillin sodium from muscle plus skin of olive flounder (n?=40, water temperature, 23?°C) was 12 d (276 degree days).

5.?Amoxicillin sodium had small MICs against Streptococcus iniae (0.008–0.06?μg/ml) and Streptococcus parauberis (0.03–1.0?μg/ml), whereas higher concentrations were required to inhibit Edwardsiella tarda isolates (0.06–16?μg/ml).

6.?While large AUC_0–24?h/MIC₉₀ and C_max/MIC₉₀ ratios were obtained for S. iniae and S. parauberis, with drug concentrations in serum greater than MICs for the entire dosing interval (T?>?MIC₉₀ of 100%), the lower dose (12.5?mg/kg) could not achieve target values of the PK–pharmacodynamic (PD) indices for E. tarda isolates, suggesting the need for higher doses to combat pathogenic bacteria with large MICs.     

Pharmacokinetic study of methylnaltrexone after single and multiple subcutaneous administrations in healthy Chinese subjects

1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects.

2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3?mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15?mg/kg of MNTX bromide injection every 48?h, in total five administrations. The concentrations of MNTX in plasma were quantified by LC–MS/MS.

3. After single s.c. administrations of 0.075, 0.15, and 0.3?mg/kg of MNTX bromide, C_max values of MNTX were 93.5?±?28.6, 191?±?37, and 364?±?54?ng/mL, respectively, and AUC_0–∞ were 88.8?±?8.8, 181?±?16, and 357?±?34?ng?h/mL, respectively. The t_1/2 of MNTX was about 7.7?h. After multiple doses administration, the C_max, C_av, AUC_ss, and MRT_0–∞ values were 191?±?50, 3.79?±?0.40?ng/mL, 182?±?19?ng?h/mL, and 3.56?±?1.17?h, respectively.

4. Methylnaltrexone bromide displayed dose-proportional pharmacokinetics in the dose range of 0.075–0.3?mg/kg. After multiple doses administration, t_1/2 was slightly prolonged, with the cumulative factor of 1.02. This study provides a pharmacokinetic reference after a single dose and multiple doses of MNTX bromide in Chinese subjects.     

Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6

1.?This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects.

2.?In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study.

3.?The geometric mean (per cent coefficient of variability) area under the concentration–time curve from time zero to infinity (AUC_inf) and maximum plasma concentration (C_max) were 1662?ng?h/mL (26%) and 21.51?ng/mL (27%), respectively, for dacomitinib and 469?ng?h/mL (65%) and 5.54?ng/mL (79%) for PF-05199265. Median times to C_max were 8 and 4?h postdose for dacomitinib and PF-05199265, respectively; mean terminal half-life of dacomitinib was 62.7?h. Geometric mean apparent clearance and volume of distribution of dacomitinib were 27.06?L/h and 2415?L, respectively. The metabolite PF-05199265-to-dacomitinib ratios were 0.2907 for AUC_inf and 0.2656 for C_max.

4.?Dacomitinib total (AUC_inf) and peak exposures (C_max) were similar among subjects with different CYP2D6 genotypes, whereas both parameters for PF-05199265 were higher in extensive metabolisers (n?=?5) versus intermediate metabolisers (n?=?8).     

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.     

Differential pharmacokinetic drug-drug interaction potential of eletriptan between oral and subcutaneous routes

Abstract

1. Pharmacokinetic drug-drug interaction (DDI) data is important from a label claim either in combination drug usage or in polypharmacy situation.

2. Eletriptan undergoes first pass related metabolism through CYP3A4 enzyme to form pharmacologically active N-desmethyl metabolite.

3. Differential DDI interaction of the concomitant oral dosing of ketoconazole (20.1?mg/kg), a CYP3A4 inhibitor, with oral (4.2?mg/kg) or subcutaneous dose (2.1?mg/kg) of eletriptan was evaluated in male Sprague Dawley rats. Serial pharmacokinetic samples were collected and simultaneously analysed for eletriptan/N-desmethyl eletriptan using validated assay. Non-compartmentally derived pharmacokinetic parameters for various treatments were analysed statistically.

4. After oral eletriptan in presence of ketoconazole, C_max (40 vs. 32?ng/mL alone) and AUC_inf (81 vs. 24?ng.h/mL alone) of eletriptan increased; the formation of N-desmethyl eletriptan decreased (C_max=1.1?ng/mL, 3.9%) with ketoconazole as compared to without treatment (C_max=3.7?ng/mL, 11.2%). After subcutaneous eletriptan in presence of ketoconazole, there was no change in C_max (153 vs.152?ng/mL) or AUC_inf (267 vs. 266?ng.h/mL) of eletriptan. Formation of N-desmethyl eletriptan after the subcutaneous dose was determined at few intermittent time points with/without ketoconazole.

5. Preclinical data support differential DDI of eletriptan when dosed oral vs. subcutaneous, which need to be evaluated in a clinical setting.     

Pharmacokinetics,distribution, and disposition of esaxerenone,a novel,highly potent and selective non-steroidal mineralocorticoid receptor antagonist,in rats and monkeys

1.?Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys.

2.?Following intravenous dosing of esaxerenone at 0.1–3?mg/kg, the total body clearance and the volume of distribution were 3.53–6.69?mL/min/kg and 1.47–2.49?L/kg, respectively, in rats, and 2.79–3.69?mL/min/kg and 1.34–1.54?L/kg, respectively, in monkeys. The absolute oral bioavailability was 61.0–127% in rats and 63.7–73.8% in monkeys.

3.?After oral administration of [¹⁴C]esaxerenone, the radioactivity was distributed widely to tissues, with the exception of a low distribution to the central nervous system. Both in rats and in monkeys, following oral administration of [¹⁴C]esaxerenone the main excretion route of the radioactivity was feces.

4.?Five initial metabolic pathways in rats and monkeys were proposed to be N-dealkylation, carboxylation, hydroxymethylation, O-glucuronidation, and O-sulfation. The oxidized metabolism was predominant in rats, while both oxidation and glucuronidation were predominant in monkeys.     

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.     

The comparative disposition and metabolism of dolutegravir,a potent HIV-1 integrase inhibitor,in mice,rats, and monkeys

Abstract

1.?Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12?mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28?L/kg, respectively) with terminal elimination half-life approximately 6?h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension.

2.?Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species.

3.?Following oral administration to rats, [¹⁴C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24?h.

4.?The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.     

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.