A sensitive method for determination of platycodin d in rat plasma using liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study

Platycodin D (PD), a major component isolated from the root of Platycodon grandiflorum, is widely used in traditional Chinese medicine. A sensitive rapid analytical method was established and validated to determine the PD in rat plasma. This method was further applied to assess the pharmacokinetics of PD in rats following administration of a single dose. Liquid chromatography tandem mass spectrometry (LC/MS/MS) in multiple reaction monitoring mode (MRM) was used in the method, and tubeimoside I was used as the internal standard (IS). A simple protein precipitation based on methanol (MeOH) was employed. The combination of a simple sample cleanup and short chromatographic running time (4?min) increased the throughput of the method substantially. The method was validated over the range of 0.5-1000?ng/mL with a correlation coefficient >?0.99. The lower limit of quantification was 0.5?ng/mL for PD in plasma. Intra- and inter-day accuracies for PD were 90-115?% and 96-108?%, respectively, and the inter-day precision was less than 15?%. After a single oral dose of 10?mg/kg of PD, its mean peak plasma concentration ( CMAX) was 13.7?±?4.5?ng/mL at 0.5?h. The area under the plasma concentration-time curve ( AUC0-24?H) was 35.4?±?16.1?h·ng/mL, and the elimination half-life ( T1/2) was 1.48?±?0.13?h. In case of intravenous administration of PD at a dosage of 0.5?mg/kg, the area under the plasma concentration-time curve ( AUC0-24?H) was 2203?±?258?h?·?ng/mL, and the elimination half-life (T?) was 6.57?±?0.70?h. Based on the results, the oral bioavailability of PD in rats at 10?mg/kg is 0.079?%.     

Alteration of the intravenous and oral pharmacokinetics of valsartan via the concurrent use of gemfibrozil in rats

The present study aimed to examine the potential pharmacokinetic drug interaction between valsartan and gemfibrozil. Compared with the control given valsartan (10 mg/kg) alone, the concurrent use of gemfibrozil (10 mg/kg) significantly (p < 0.05) increased the oral exposure of valsartan in rats. In the presence of gemfibrozil, the C_max and AUC of oral valsartan increased by 1.7‐ and 2.5‐fold, respectively. Consequently, the oral bioavailability of valsartan was significantly higher (p < 0.05) in the presence of gemfibrozil compared with that of the control group. Furthermore, the intravenous pharmacokinetics of valsartan (1 mg/kg) was also altered by pretreatment with oral gemfibrozil (10 mg/kg). The plasma clearance of valsartan was decreased by two‐fold in the presence of gemfibrozil, while the plasma half‐life was not altered. In contrast, both the oral and intravenous pharmacokinetics of gemfibrozil were not affected by the concurrent use of valsartan. The cellular uptake of valsartan and gemfibrozil was also investigated by using cells overexpressing OATP1B1 or OATP1B3. Gemfibrozil and gemfibrozil 1‐O‐β glucuronide inhibited the cellular uptake of valsartan with IC₅₀ values (µm ) of 39.3 and 20.4, respectively, in MDCK/OATP1B1, while they were less interactive with OATP1B3. The cellular uptake of gemfibrozil was not affected by co‐incubation with valsartan in both cells. Taken together, the present study suggests the potential drug interaction between valsartan and gemfibrozil, at least in part, via the OATP1B1‐mediated transport pathways during hepatic uptake. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.     

Variability of oral bioavailability for low dose methotrexate in rats.

The effects of food, antibiotics, diclofenac sodium (DS) and methotrexate (MTX) on oral bioavailability (BA) of MTX were examined in rats. Feeding didn't vary the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but enhanced those after oral dosing, and the oral BA. The twice daily oral doses of 40 mg/kg neomycin sulfate (NS) or mixed antibiotics (200 mg/kg NS + 200 mg/kg streptomycin sulfate + 200 mg/kg bacitracin) for 5 days didn't influence the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but induced the decreased Cmax and the delayed MRT after oral dosing. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats orally dosed with 1 or 5 mg/kg/day DS for 4 days were similar to those in the control rats, while the pre-treatment of 25 mg/kg/day DS delayed the elimination of MTX but didn't change the oral BA. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats, which received the intermittent oral doses of 7.5 mg/kg/3 doses/week MTX for 4 weeks, were comparable to those in the control rats, but the daily pre-treatment of 0.2 mg/kg/day MTX for 4 weeks increased the plasma concentrations after oral dosing, and the BA.     

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.     

Effects of baicalein on the pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen,in rats: Possible role of cytochrome p450 3A4 and P-glycoprotein inhibition by baicalein

The purpose of this study was to investigate the effects of baicalein on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats. Tamoxifen and baicalein interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in baicalein being taken concomitantly with tamoxifen as a combination therapy to treat orprevent cancer diseases. Pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined in rats after an oral administration of tamoxifen (10 mg/kg) to rats in the presence and absence of baicalein (0.5, 3, and 10 mg/kg). Compared to the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve and the peak plasma concentration of tamoxifen were significantly increased by 47.6–89.1% and 54.8–100.0%, respectively. The total body clearance was significantly decreased (3 and 10 mg/kg) by baicalein. Consequently, the absolute bioavailability of tamoxifen in the presence of baicalein (3 and 10 mg/kg) was significantly increased by 47.5–89.1% compared with the oral control group (20.2%). The metabolite-parent AUC ratio of tamoxifen was significantly reduced, implying that the formation of 4-hydroxytamoxifen was considerably affected by baicalein. Baicalein enhanced the oral bioavailability of tamoxifen, which may be mainly attributable to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the small intestine and/or in the liver, and inhibition of the P-gp efflux pump in the small intestine and/or reduction of total body clearance by baicalein.     

Effects of myricetin on the bioavailability of doxorubicin for oral drug delivery in Rats: Possible role of CYP3A4 and P-glycoprotein inhibition by myricetin

The purpose of this study was to investigate the effect of oral myricetin on the bioavailability and pharmacokinetics of orally and intravenously administered doxorubicin (DOX) in rats for oral delivery. The effect of myricetin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Myricetin inhibited CYP3A4 enzyme activity with 50% inhibition concentration of 7.8 μM. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of DOX were determined in rats after oral (40 mg/kg) or intravenous (10 mg/kg) administration of DOX to rats in the presence and absence of myricetin (0.4, 2 or 10 mg/kg). Compared to the control group, myricetin significantly (p < 0.05, 2 mg/kg; p < 0.01, 10 mg/kg) increased the area under the plasma concentration-time curve (AUC, 51–117% greater) of oral DOX. Myricetin also significantly (p < 0.05, 2 mg/kg; p < 0.01, 10 mg/kg) increased the peak plasma concentration of DOX. Consequently, the absolute bioavailability of DOX was increased by myricetin compared to that in the control group, and the relative bioavailability of oral DOX was increased by 1.51- to 2.17-fold. The intravenous pharmacokinetics of DOX were not affected by the concurrent use of myricetin in contrast to the oral administration of DOX. Accordingly, the enhanced oral bioavailability in the presence of myricetin, while there was no significant change in the intravenous pharmacokinetics of DOX, could be mainly due to the increased intestinal absorption via P-gp inhibition by myricetin rather than to the reduced elimination of DOX. These results suggest that the increase in the oral bioavailability of DOX might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and to reduced first-pass metabolism of DOX due to inhibition of CYP3A in the small intestine and/or in the liver by myricetin.     

Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats: a possible role of P-glycoprotein and CYP3A4 inhibition by baicalein

The reduced bioavailability of nimodipine after oral administration might not only be due to the metabolizing enzyme cytochrome P450 3A4(CYP3A4) but also to the P-glycoprotein efflux transporter in the small intestine. The aim of this study was to investigate the effects of baicalein on the pharmacokinetics of nimodipine in rats. The effect of baicalein on P-glycoprotein and CYP3A4 activity was evaluated. A single dose of nimodipine was administered intravenously (3 mg/kg) and orally (12 mg/kg) to rats in the presence and absence of baicalein (0.4, 2 and 8 mg/kg). Baicalein inhibited CYP3A4 enzyme activity in a concentration-dependent manner, with a 50% inhibition concentration (IC(50)) of 9.2 μM. In addition, baicalein significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-glycoprotein. Baicalein significantly altered the pharmacokinetics of orally administered nimodipine. Compared to the oral control group given nimodipine alone, the area under the plasma concentration-time curve (AUC(0-∞)) and the peak plasma concentration (C(max)) of nimodipine significantly increased (p < 0.05 for 2 mg/kg; p < 0.01 for 8 mg/kg). Consequently, the absolute bioavailability of nimodipine in the presence of baicalein (2 and 8 mg/kg) was 31.0-35.3%, which was significantly enhanced (p < 0.05 for 2 mg/kg; p < 0.01 for 8 mg/kg) compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.39- to 1.58-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine were not affected by baicalein in contrast to those of oral nimodipine. Baicalein significantly enhanced the oral bioavailability of nimodipine, which may be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and/or in the liver and the inhibition of the P-glycoprotein efflux pump in the small intestine by baicalein. The increase in oral bioavailability of nimodipine in the presence of baicalein should be taken into consideration as a potential drug interaction between nimodipine and baicalein.     

Effects of prednisolone on the pharmacokinetics of loratadine after oral and intravenous administration of loratadine in rats

The present study aims to investigate the effects of prednisolone on the pharmacokinetics of orally and intravenously administered loratadine in rats. A single dose of loratadine was administered orally (4 mg/kg) and intravenously (1 mg/kg) in the presence or absence of prednisolone (0.2 or 0.8 mg/kg). Compared to the oral control group, prednisolone (0.2 mg/kg, p < 0.05; 0.8 mg/kg, p < 0.01) significantly increased the area under the plasma concentrationtime curve of orally administered loratadine by 54.0–96.4%. After oral administration, the peak plasma concentration of loratadine was significantly (0.2 mg/kg, p < 0.05; 0.8 mg/kg, p < 0.01) increased by 20.9–65.3% in the presence of prednisolone. Consequently, the relative bioavailability of loratadine was increased by 1.54- to 1.96-fold. Compared to the intravenous control group, the presence of prednisolone significantly (0.8 mg/kg, p < 0.05) increased the area under the plasma concentration-time curve of loratadine. Prednisolone enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine may be due to inhibition both cytochrome P450 3A4-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or liver by the presence of prednisolone.     

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 of lithospermic acid B isolated from Salvia miltiorrhiza in rats

The absorption and pharmacokinetics of an active component of Salvia miltiorrhiza, lithospermic acid B (LSB), was investigated after intravenous and oral administration of doses of 10 or 50 mg LSB/kg to rats. Concentrations of LSB were determined by a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay method. After intravenous administration of 50 mg/kg, dose-normalized (10 mg/kg) area under the curve (AUC) (993 microg.min/ml) was significantly greater than that at 10 mg/kg (702 microg.min/ml). The slower clearance Cl-at 50 mg/kg could be due to saturable metabolism of LSB in rats, and this could be supported by significantly slower Cl(NR) and significantly greater 24-h urinary excretion of LSB at 50 mg/kg than at 10 mg/kg. Following oral administration of LSB, the extent of LSB recovered from the entire gastrointestinal tract at 24 h ranged from 41.2% to 23.3%. Although LSB was not detected (limit of quantitation 10 ng/ml) in plasma after oral dose of 10 mg/kg, the absolute oral bioavailability at 50 mg/kg was 5%. Since LSB was shown to have low permeability through the Caco-2 cell monolayers, the low bioavailability of LSB could be due to poor absorption and metabolism.     

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.     

effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite,desacetyldiltiazem, in rats

The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg x kg(-1)) to rats pretreated with atorvastatin (0.5 or 2.0 mg x kg(-1)). Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly (p < 0.05, 0.5 mg x kg(-1); p < 0.01, 2.0 mg x kg(-1)) increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with 0.5 mg x kg(-1) atorvastatin, and 1.77-fold in rats pretreated with 2.0 mg x kg(-1) atorvastatin. Consequently, absolute bioavailability values of diltiazem pretreated with atorvastatin (8.4-10.6%)were significantly higher (p < 0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p < 0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (M.R.) in the presence of atorvastatin (0.5 or 2.0 mg x kg(-1)) was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.     

The pharmacokinetics of Casodex in laboratory animals

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs.

2. The binding of ¹⁴C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values >95%; in dog there was evidence for decreased binding at concentrations >12 μg/ml.

3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1?mg/kg to 10% and 12% at 250?mg/kg; in dog bioavailability decreased from 100% at 0.1?mg/kg to 31% at 100?mg/kg.

4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10?mg/kg but not at 250?mg/kg; in dog appreciable accumulation (9–12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10?mg/kg, but at 100?mg/kg the accumulation ratio was much lower (4-fold).     

Effects of morin on the bioavailability of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats

This study examined the effect of morin on the bioavailability and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, in rats. A single dose of tamoxifen was administered to rats intravenously (2 mg/kg) or orally (10 mg/kg), with or without morin (3 or 10 mg/kg). The presence of morin significantly altered the pharmacokinetics of the orally administered tamoxifen. Compared with the oral control group (given tamoxifen alone), the total body clearance (CL/F) of tamoxifen in the presence of morin was significantly reduced (by 35.9-40.8%, p<0.01). The area under the plasma concentration-time curve (AUC(0-infinity)) and the peak plasma concentration (Cmax) of tamoxifen significantly (p<0.05 for 3 mg/kg of morin, p<0.01 for 10 mg/kg of morin) increased by 50.6-68.9% and 65.1-80.9%, respectively. Consequently, the absolute bioavailability (AB) of tamoxifen in the presence of morin was 37.4-40.5%, which was enhanced significantly (p<0.05) compared with the oral control group (23.9%). The relative bioavailability (RB) of tamoxifen was 1.56 to 1.68 times higher than the control group. The increased bioavailability of tamoxifen is likely to be due to the decrease in the first-pass metabilism by the intestines and liver. Morin at a dose of 10 mg/kg significant increased the AUC(0-infinity), of 4-hydroxytamoxifen (by 50.9%, p<0.05) but the metabolite:parent ratio (MR) of 4-hydroxytamoxifen was not altered significantly, suggesting that the formation of 4-hydroxytamoxifen is not affected considerably by morin. The increased bioavailability of tamoxifen in the presence of morin should be taken into consideration for dosage regimens due to potential drug interaction.     

The pharmacokinetics of pirtenidine in the rat and dog

1. Pharmacokinetic studies on the topical antimicrobial agent, pirtenidine, have been conducted in male Sprague-Dawley rats and beagle dogs, using a validated h.p.l.c. method with u.v. detection to measure the drug in plasma.

2. Following a single i.v. bolus dose to the rat (equivalent to 1.35 mg base/kg) or dog (equivalent to 0.23 mg base/kg), the drug was extensively distributed with an apparent volume of distribution of 8.61/kg in rat and 3.31/kg in dog. Clearance was high (rat 2.71/h/kg; dog 1.51/h/kg) which resulted in a short terminal half-life in both species (2.2 and 1.5 h respectively).

3. Following a single oral dose to rats (equivalent to 4.5 mg base/kg) plasma pirtenidine concentrations were generally below the minimum quantifiable level of the analytical method (1 ng/ml). A maximum possible bioavailability of 0.3% was estimated.

4. After administering the same oral dose to dogs plasma concentrations rose slowly (t1/2abs=1.2 h) to a peak (49.7 ng/ml) at 5.0 h post-dose. The terminal elimination half-life was 2.1 h. The absolute bioavailability was 10%.     

Effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats

The present study aimed to investigate the effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats. The pharmacokinetic parameters of verapamil were measured after an oral (9 mg/kg) or intravenous (3 mg/kg) administration of verapamil to rats in the presence and absence of atorvastatin. Compared with the control given verapamil alone, the concurrent use of 1.5 mg/kg of atorvastatin significantly increased the oral exposure of verapamil in rats. The AUC and C(max) of verapamil increased by 70% and 61%, respectively in the presence of atorvastatin (1.5 mg/kg), while there was no significant change in T(max) and the terminal plasma half-life (T(1/2)) of verapamil. Accordingly, the presence of atorvastatin significantly (p<0.05) increased the bioavailability of verapamil in rats. In contrast, atorvastatin had no effect on any pharmacokinetic parameters of verapamil given intravenously, implying that atorvastatin may improve the oral bioavailability of verapamil by reducing the prehepatic extraction of verapamil most likely mediated by P-gp and/or CYP3A4. In conclusion, coadministration of atorvastatin significantly enhanced the oral exposure of verapamil in rats without a change in the systemic clearance of intravenous verapamil, suggesting a potential drug interaction between verapamil and atorvastatin via the modulation of prehepatic extraction.     

Species differences in oral bioavailability of methotrexate between rats and monkeys

The contributions of incomplete absorption and a first-pass effect to the low bioavailability (BA) of methotrexate (MTX) were evaluated pharmacokinetically in rats and monkeys which respectively have a lower and higher aldehyde oxidase (AO) activity than humans. Plasma concentration profiles of MTX in rats showed linear and nonlinear pharmacokinetics respectively after intravenous (i.v.) and oral dosing of 0.1, 0.5 or 2.5 mg/kg MTX. In rats, most of the dose was excreted as the parent compound into bile and urine after i.v. dosing of 0.5 mg/kg MTX, while the radioactivity was largely eliminated in expired air after oral dosing of 0.5 mg/kg 14C-MTX. Elimination in expired air fell markedly following antibiotics treatment. 7-Hydroxymethotrexate (7-OH-MTX), formed from MTX by AO, was detected in monkey plasma after i.v. and oral dosing of 0.5 mg/kg MTX, but not in rat plasma. The ratio of the cumulative urinary excretion of 7-OH-MTX to MTX in monkeys was higher after oral dosing than after i.v. dosing. The low BA in rats (10% at 0.5 mg/kg) was shown to be mainly due to incomplete absorption, including limited absorption and degradation to 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamic acid (Glu) by the carboxypeptidase of intestinal bacteria. The low BA in monkeys (5% at 0.5 mg/kg) was shown to be mainly due to the extensive first-pass effect, including metabolism to 7-OH-MTX.     

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

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. 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. 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%. 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,biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration

Context: Isoliquiritigenin (ISL) has been shown to exhibit a variety of biological activities. However, there is little research on the pharmacokinetic behavior and tissues distribution of ISL.

Objective: Pharmacokinetics, biodistribution and bioavailability of ISL after intravenous and oral administration were determined by systematic investigation in Sprague–Dawley rats.

Materials and methods: ISL was dissolved in medicinal ethanol-Tween 80–0.9% sodium chloride saline in a volume ratio of 10:15:75. The ISL solution was injected in rats via a tail vein at a single dose of 10, 20 and 50?mg/kg and administered orally in rats at a single dose of 20, 50 and 100?mg/kg, respectively. Blood samples were collected at time intervals of 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8 and 12?h after intravenous injection. Tissues of interests in mice were collected immediately at each determined time point (0.5, 1, 2, 3 and 6?h) after cervical dislocation.

Results: The dose-normalized AUC values were 7.3, 7.6 and 8.7?μg?×?h/ml (calculated based on the dose of 10?mg/kg) for intravenous doses of 10, 20 and 50?mg/kg, respectively. The elimination half-lifes (t_1/2λ) were 4.9, 4.6 and 4.8?h at 10, 20 and 50?mg/kg intravenous doses, respectively. The F values were 29.86, 22.70, 33.62% for oral doses of 20, 50 and 100?mg/kg, respectively. Liver, heart and kidney were major distribution tissues of ISL in mice. The plasma protein binding of ISL in rats was 43.72%.

Conclusion: The work may useful for further study of the bioactive mechanism of ISL.     

Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite,norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (C_max) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T_max) and the terminal half-life (t_1/2) of verapamil in the presence of lovastatin. The AUC and C_max of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.