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.     

Leishmanicidal candidate LASSBio-1736, a cysteine protease inhibitor with favorable pharmacokinetics: low clearance and good distribution

Abstract

1.?LASSBio-1736 ((E)-1-4(trifluoromethyl) benzylidene)-5-(2-4-dichlorozoyl) carbonylhydrazine) is proposed to be an oral cysteine protease leishmanicidal inhibitor.

2.?This work aimed to investigate plasma pharmacokinetics, protein binding and tissue distribution of LASSBio-1736 in male Wistar rats.

3.?LASSBio-1736 was administered to male Wistar rats at doses of 3.2?mg/kg intravenously and 12.6?mg/kg oral and intraperitoneal. The individual plasma-concentration profiles were determined by HPLC-UV and evaluated by non-compartmental and population pharmacokinetic analysis (Monolix 2016R1, Lixoft). Tissue distribution was evaluated after iv injection of 3.2?mg/kg drug by non-compartmental approach.

4.?After intravenous administration, Vd_ss (1.79?L/kg), t _½ (23.1?h) and CL_tot (56.1?mL/h/kg) were determined, and they were statistically similar (α?=0.05) to oral and intraperitoneal pharmacokinetic parameters. The plasma profiles obtained after intravenous, oral and intraperitoneal administration of the compound were best fitted to a three-compartment and one-compartment open model with first-order absorption.

5.?The intraperitoneal and oral bioavailability were around 40 and 15%, respectively.

6.?Liver, spleen and skin tissues showed penetration of 340, 130 and 40%, respectively, with t _½ like plasma values.

7.?LASSBio-1736 protein binding was 95?±?2%.

8.?The t _½, CL_tot and tissue distribution of the compound agreed with the desired drug characteristics for leishmanicidal activity.     

Stereoselective pharmacokinetic study of rhynchophylline and isorhynchophylline epimers in rat plasma by liquid chromatography–tandem mass spectrometry

1.?In this study, the stereoselective pharmacokinetics of rhynchophylline (RIN) and isorhynchophylline (IRN) in rat plasma were investigated using liquid chromatography–tandem mass spectrometry (LC–MS/MS).

2.?A rapid, robust and sensitive LC–MS/MS method for simultaneous quantification of RIN and IRN in rat plasma was established and validated. Chromatographic separation was performed on a Poroshell 120 EC-C₁₈ column under a gradient elution with methanol and water containing 0.01% ammonia as mobile phase. Calibration curve was linear over a concentration range of 1–2000?ng/mL for both epimers.

3.?After intravenous administration, there was no apparent difference in pharmacokinetic parameters between two epimers. However, after oral administration, RIN showed remarkable higher plasma exposure than IRN. The bioavailability, C_max and AUC_0–t of RIN were about 9.2-fold, 6.4-fold and 9.1-fold higher than those of IRN at 10?mg/kg, and 7.8-fold, 4.3-fold and 7.7-fold at 20?mg/kg, respectively. Additionally, with dosage enhanced from 10?mg/kg to 20?mg/kg, the plasma concentrations of RIN or IRN increased significantly and the bioavailability enhanced about three times.

4.?In conclusion, the results of this work demonstrated for the first time that the pharmacokinetics of RIN and IRN have stereoselectivity.     

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.     

Tissue time course and bioavailability of the pyrethroid insecticide bifenthrin in the Long-Evans rat

1.?Pyrethroids are neurotoxic and parent pyrethroid appears to be toxic entity. This study evaluated the oral disposition and bioavailability of bifenthrin in the adult male Long-Evans rat.

2.?In the disposition study, rats were administered bifenthrin (0.3 or 3?mg/kg) by oral gavage and serially sacrificed (0.25?h to 21 days). Blood, liver, brain and adipose tissue were removed. In the bioavailability study, blood was collected serially from jugular vein cannulated rats (0.25 to 24?h) following oral (0.3 or 3?mg/kg) or intravenous (0.3?mg/kg) administration of bifenthrin. Tissues were extracted and analyzed for bifenthrin by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

3.?Bifenthrin concentration in blood and liver peaked 1–2-h postoral administration and were approximately 90?ng/ml (or g) and 1000?ng/ml (or g) for both tissues at 0.3 and 3?mg/kg, respectively. Bifenthrin was rapidly cleared from both blood and liver. Brain concentrations peaked at 4–6?h and were lower than in blood at both doses (12 and 143?ng/g). Bifenthrin in adipose tissue peaked at the collected time points of 8 (157?ng/g) and 24 (1145?ng/g) h for the 0.3 and 3?mg/kg doses, respectively and was retained 21 days postoral administration. Following intravenous administration, the blood bifenthrin concentration decreased bi-exponentially, with a distribution half-life of 0.2?h and an elimination half-life of 8?h. Bifenthrin bioavailability was approximately 30%. These disposition and kinetic bifenthrin data may decrease uncertainties in the risk assessment for this pyrethroid insecticide.     

Pharmacokinetics,dose proportionality and permeability of S002-333 and its enantiomers,a potent antithrombotic agent,in rabbits

Abstract

1.?S002-333 [(2-(4′-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide)] is a novel and potent antithrombotic active agent. The present work investigates the pharmacokinetics, bioavailability, dose proportionality and permeability of the racemate, S002-333 in male New Zealand White (NZW) rabbits.

2.?Rabbits were administered single intravenous (i.v.) (2?mg/kg) and three oral doses of 10, 20 and 40?mg/kg of S002-333, respectively, at different occasions to evaluate dose proportionality. Serial blood samples were collected and analyzed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Since S002-333 is a racemate consisting of S004-1032 (R) and S007-1558 (S), same samples were analyzed using a chiralcel column so as to evaluate the respective enantiomers.

3.?The peak plasma concentration, after oral administration, occurred at ～10?h post-dose. The clearance (CL) and volume of distribution (V_d) after i.v. dose were found to be 3.05?±?0.09?l/h/kg and 6.73?±?1.16?l/kg, respectively. The absolute oral bioavailability of S002-333 was 16.32%, whereas it was 6.62 and 5.90% for R- and S-enantiomers, respectively. The absolute bioavailability of 10, 20 and 40?mg/kg doses were found to be 27.91, 14.39 and 16.91%, respectively. The PAMPA (parallel artificial membrane permeability assay) assay shows that S002-333 has a low-passive permeability at gastric and intestinal environment.

4.?In conclusion, S002-333 has low-passive permeability, low CL and large V_d. The R-enantiomer has a “slightly” greater bioavailability than the S-enantiomer.     

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,pharmacodynamics and food effect of LB30870, a novel direct thrombin inhibitor,after single oral doses in healthy men

Abstract

1.?The safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of LB30870, a new selective thrombin inhibitor, were studied in 16 healthy men.

2.?A double-blind, placebo-controlled single ascending dose study was done at oral doses of 5, 15, 30, 60, 120, and 240?mg under fasting conditions. An open, randomized, balanced cross-over food effect study was done at 60?mg dose. Plasma and urinary concentrations were measured up to 48?h post-dose. Coagulation and thrombin activity markers were measured at selected time points.

3.?C_max of LB30870 was at 1.3–3.0?h post-dose with a mean apparent terminal half-life (t_1/2) of 2.8–4.1?h. AUC after doses above 15?mg appeared greater than dose-proportional. In fed state, AUC showed 80% reduction relative to fasting condition.

4.?At doses 60 and 120?mg, peak activated partial thromboplastin time (aPTT) increased by 1.5- and 2-fold, respectively, from baseline. The aPTT and international normalized ratio (INR) were concentration-dependent, with less within-individual variability than ecarin clotting time (ECT), prothrombin time (PT), or thrombin time (TT).

5.?Single oral doses of LB30870 up to 240?mg were well tolerated. The food effect must be overcome if LB30870 is to be used as an oral anti-coagulant.     

Pharmacokinetics,metabolism, and excretion of cycloastragenol,a potent telomerase activator in rats

1.?The objective of this study was to investigate the pharmacokinetics, excretion, and metabolic fate of cycloastragenol (CA) in rats.

2.?An LC-MS method was developed and used to quantify CA in biological samples. Rats were orally administrated with CA at 10, 20, and 40?mg/kg or intravenously administrated at 10?mg/kg to determine pharmacokinetic parameters of CA. For excretion experiment, urine, feces, and bile were collected at 24?h after oral administration (40?mg/kg), also at 12?h after intravenous administration (10?mg/kg). An LC-MS/MS method was developed to identify the metabolites of CA.

3.?The results showed that the oral bioavailability of CA was about 25.70% at 10?mg/kg. CA was excreted through bile and feces and eliminated predominantly by the kidney in rats. It also might exist an enterohepatic circulation of CA in rats. CA could be metabolized widely in vivo in rat, seven, six, and one phase I metabolites were found in feces, urine, and bile samples respectively, but no phase II metabolite was found.

4.?In summary, this study defined pharmacokinetics characteristics of CA, described its excretion, and established its in vivo metabolism in rats.     

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.     

Pharmacokinetic comparisons of Paeoniflorin and Paeoniflorin-6'O-benzene sulfonate in rats via different routes of administration

1.?The pharmacokinetics study of Paeoniflorin (Pae) and its acylated derivative (CP-25) was performed.

2.?The structure of CP-25 was identified by mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). The rats were injected with CP-25(6, 12, 24?mg/kg) and orally treated with CP-25 (32, 64, 128?mg/kg), respectively. An high-performance liquid chromatography (HPLC) assay was developed to determine the plasma concentrations of Pae and CP-25.

3.?The results of MS and NMR showed that the acylated product was Pae-6'O-benzene sulfonate (CP-25). The plasma levels in oral CP-25 groups were detectable, whereas those of Pae in the oral groups (25 and 50?mg/kg) were undetectable. More specifically, the C_max values of oral CP-25 were 0.12, 0.19 and 0.44?μg/ml, and the corresponding t_1/2β of CP-25 were 1.44, 2.12 and 2.11?h, respectively. In addition, the t_1/2β values of intravenous CP-25 were 161.99, 152.81 and 153.76?min, respectively.

4.?Compared with the venous pharmacokinetics parameters of Pae, those of the t_1/2β, MRT, Vd and CL/F in the CP-25 groups increased noticeably. As expected, compared with oral parameters of Pae, those of t_1/2a, t_1/2β, AUC, MRT and Vd in the CP-25 group increased obviously. Finally, the absolute bioavailability of Pae and CP-25 were 3.6 and 10.6%, respectively.

5.?Our results indicate that CP-25 is characterized by improved absorption, well distribution, lower clearance, long mean residence time, and moderate bioavailability in rats.     

Pharmacokinetics of lurasidone,a novel atypical anti-psychotic drug,in rats

1. This study aimed to characterise the pharmacokinetics of lurasidone, a new atypical anti-psychotic drug, in rats after intravenous and oral administration at dose range 0.5–2.5 and 2.5–10?mg/kg, respectively. Moreover, tissue distribution, liver microsomal stability and plasma protein binding were estimated.

2. After intravenous injection, systemic clearance, steady-state volumes of distribution and half-life remained unaltered as a function of dose with values in the range 22.1–27.0?mL/min/kg, 2,380–2,850?mL/kg and 229–267?min, respectively. Following oral administration, absolute oral bioavailability was not dose dependent with approximately 23%. The recoveries of lurasidone in urine and bile were 0.286% and 0.0606%, respectively.

3. Lurasidone was primarily distributed to nine tissues (brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose) and tissue-to-plasma ratios of lurasidone were ranged from 1.06 (brain) to 9.16 (adipose). Further, lurasidone was unstable in rat liver microsome and the plasma protein binding of lurasidone was concentration independent with approximately 99.6%.

4. In conclusion, lurasidone showed dose-independent pharmacokinetics at an intravenous dose of 0.5–2.5?mg/kg and an oral dose of 2.5–10?mg/kg. Lurasidone was primarily distributed to nine tissues and appeared to be primarily eliminated by its metabolism.

     

Pharmacokinetics of barnidipine hydrochloride,a new dihydropyridine calcium channel blocker,in the rat,dog and human

1. The pharmacokinetics of a new calcium antagonist barnidipine hydrochloride, a stereochemically pure enantiomer, was studied after intravenous and oral dosing to the rat and dog, and oral to man.

2. After intravenous dosing, plasma concentrations of barnidipine hydrochloride declined bi-exponentially with the terminal half-lives of 0·6?h in the rat and 4·1?h in the dog. The blood clearance was 5·21/h/kg in the rat and 3·31/h/kg in the dog, and was comparable with hepatic blood flow in both species.

3. After oral dosing, plasma concentrations of barnidipine hydrochloride peaked rapidly (0·3-0·4?h in the rat and dog, 1·0–1·6?h in man). C_max and AUC rose non-linearly with increasing doses in all three species.

4. The absolute bioavailability was low (11–18% in the rat and 6–9% in the dog), suggesting a marked first-pass metabolism.     

Investigation of the influence of glycyrrhizin on the pharmacokinetics of celastrol in rats using LC-MS and its potential mechanism

1.?The aim of this study was to investigate the effects of glycyrrhizin on the pharmacokinetics of celastrol in rats.

2.?Twelve male Sprague–Dawley rats were randomly assigned to two groups: control group and test group. Test group was pretreated with glycyrrhizin at a dose of 100?mg/kg/day for 10 days, and then the two groups were orally administered with celastrol at a dose of 1?mg/kg. The concentration of celastrol was determined using a sensitive and reliable LC-MS method.

3.?The results showed that glycyrrhizin could significantly decrease the plasma concentration (from 64.36?ng/mL to 38.42?ng/mL) and AUC_0?t (from 705.39 to 403.43?μg·h/L) of celastrol in rats. To investigate its potential mechanism, the effects of glycyrrhizin on the transport and metabolic stability of celastrol were investigated using Caco-2 cell monolayer transwell model and rat liver microsome incubation systems. The Caco-2 cell monolayer transwell experiments indicated that glycyrrhizin could increase the efflux ratio of celastrol (4.02 versus 6.51). However, the rat liver microsome incubation experiments showed that glycyrrhizin could significantly increase the intrinsic clearance rate of celastrol from 20.3?±?3.37 to 38.8?±?4.18?μL/min/mg protein.

4.?In conclusion, these results indicated that the herb–drug interaction between glycyrrhizin and celastrol might occur when they were coadministered.     

Pharmacokinetics of chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent,in rats

Abstract

1.?Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1–8?mg/kg) or CRD (1.1–4.5?mg/kg) and their equivalent dose of DA-9701 to rats.

2.?Dose-proportional AUC and dose-independent clearance (10.3–12.1?ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478–0.899%).

3.?CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5?mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.     

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 properties of trifolirhizin, (–)-maackiain, (–)-sophoranone and 2-(2,4-dihydroxyphenyl)-5,6-methylenedioxybenzofuran after intravenous and oral administration of Sophora tonkinensis extract in rats

Abstract

1.?SKI3301, a standardized dried 50% ethanolic extracts of Sophora tonkinensis, contains four marker compounds (trifolirhizin, TF; (–)-maackiain, Maack; (–)-sophoranone, SPN, and (2-(2,4-dihydroxyphenyl)-5,6-methylenedioxybenzofuran, ABF), is being developed as an herbal medicine for the treatment of asthma in Korea. This study investigates the pharmacokinetic properties of SKI3301 extract in rats.

2.?The dose-proportional AUCs suggest linear pharmacokinetics of TF, Maack, SPN and ABF in the SKI3301 extract intravenous dose range of 5–20?mg/kg. After the oral administration of 200–1000?mg/kg of the extract, TF and Maack exhibited non-linearity due to the saturation of gastrointestinal absorption. However, linear pharmacokinetics of SPN and ABF were observed.

3.?The absorptions of TF, Maack, SPN and ABF in the extract were increased relative to those of the respective pure forms due to the increased solubility and/or the decreased metabolism by other components in the SKI3301 extract.

4.?No accumulation was observed after multiple dosing, and the steady-state pharmacokinetics of TF, Maack, SPN and ABF were not significantly different from those after a single oral administration of the extract.

5.?The pharmacokinetics of TF, SPN and ABF were not significantly different between male and female rats after oral administration of the extract, but a significant gender difference in the pharmacokinetics of Maack in rats was observed.

6.?Our findings may help to comprehensively elucidate the pharmacokinetic characteristics of TF, Maack, SPN and ABF and provide useful information for the clinical application of SKI3301 extract.     

Effect of piperine on the bioavailability and pharmacokinetics of rosmarinic acid in rat plasma using UPLC-MS/MS

1.?The purpose of the present study was to investigate the effect of piperine (PP) on the pharmacokinetics of rosmarinic acid (RA) in rat plasma and to determine whether PP could enhance the oral bioavailability of RA via inhibition of its glucuronidation.

2.?The pharmacokinetic profiles of RA between oral administration of RA (50?mg/kg) alone and in combination with different oral dose PP (20, 40, 60, and 80?mg/kg) to rats were investigated via a validated UPLC/MS/MS method.

3.?The AUC and C_max of RA were significantly increased in combination with different dose PP dose dependently, especially in the presence of 60 and 80?mg/kg PP (p?4.?This study demonstrated that PP significantly improved the in vivo bioavailability of RA partly attributing to the inhibition of gut and hepatic metabolism enzymes of RA.     

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 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.