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 the prodrug thiamphenicol glycinate and its active parent compound thiamphenicol in beagle dogs following intravenous administration

1. This study investigated the pharmacokinetics of thiamphenicol glycinate (TG) and thiamphenicol (TAP) in beagles (n?=?6) after intravenous administration of 50?mg/kg TG hydrochloride. Plasma concentrations of TG and TAP were measured by a HPLC-UV method.

2. Two-compartment model was selected to describe the pharmacokinetic characteristics of TG and TAP in vivo. Main parameters were as follows: AUC_0–∞ of TAP and TG were 16,328?±?1682 µg·min/mL and 3943?±?546 µg·min/mL, respectively. The total plasma clearance (CL) of TG and TAP were 12.7?±?2.0?mL/min/kg and 2.5?±?0.3?mL/min/kg, respectively. Mean residence time (MRT) of TG and TAP were 27.5?±?3.5 and 207.2?±?20.2?min, respectively. The transformative rate constant (k_1M) from TG to TAP was 0.0477?±?0.0028?min^?1. The elimination rate constant (k_M10) from TAP was 0.0238?±?0.0044?min^?1. Coefficients of variation (CV) between observed values and predicted ones were 5.9% and 18.2%, respectively. The volume of distribution of the central compartment for TG (V_C) and TAP (V_CM) were 0.264?±?0.022?L/kg and 0.127?±?0.023?L/kg, respectively.

3. Pharmacokinetic parameters suggested that TG was presumably cleaved quickly by tissue esterase to release TAP for effectiveness in beagles after administration.

     

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.     

The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat

1. The comparative gastric toxicology and pharmacokinetics of two phenoxyisobutyrate derivatives have been evaluated in the Fischer rat.

2. After oral administration of single daily doses for 7 days, the plasma elimination half-life for bezafibrate was rapid (t_1/2 of 4–5?h) in comparison to ciprofibrate (t_1/2 of 76?h).

3. The area under the plasma drug concentration versus time curve (AUC) _0–24 (μg±?h/ml± SD) for bezafibrate (dose 125mg/kg per day) was 1553±334, which was less than half the value of 3748±358 achieved by ciprofibrate (10?mg/kg per day) after 7 days.

4. Oral administration of ciprofibrate at 10?mg/kg every 48?h produced similar sustained plasma concentrations to those achieved by bezafibrate 125?mg/kg dosed every 12?h. The AUC0–48 values (μg±h/ml±SD) achieved were 5124±450 for bezafibrate compared to 4207±240 for ciprofibrate.

5. In chronic oral multidose studies with ciprofibrate and bezafibrate, similar gastric toxicity (neuroendocrine cell hyperplasia) occurred in the rat when dose regimens were adjusted to compensate for the pharmacokinetic differences between these two drugs.     

Effects of glycyrrhizin on the pharmacokinetics of puerarin in rats

1. Puerarin has been reported to possess a wide range of pharmacological activities. This study investigated the effects of glycyrrhizin on the pharmacokinetics of puerarin in rats.

2. The pharmacokinetics of orally administered puerarin (50?mg/kg) with or without glycyrrhizin pretreatment (100?mg/kg/day for 7?days) were investigated. The plasma concentration of puerarin was determined using a sensitive and reliable LC-MS/MS method. The pharmacokinetics profiles were calculated and compared. Additionally, a Caco-2 cell transwell model was used to investigate the potential mechanism of glycyrrhizin’s effects on the pharmacokinetics of puerarin.

3. The results showed that when the rats were pretreated with glycyrrhizin, the maximum concentration (C_max) of puerarin decreased from 761.25?±?52.34 to 456.32?±?34.75?ng/mL, and the area under the concentration–time curve from zero to infinity (AUC_0–inf) also decreased from 4142.15?±?558.51 to 2503.74?±?447.57?μg·h/L. The oral clearance of puerarin increased significantly from 12.20?±?1.53 to 20.47?±?3.25?L/h/kg (p?4. In conclusion, these results indicated that glycyrrhizin could affect the pharmacokinetics of puerarin, possibly by decreasing the systemic exposure of puerarin by inducing the activity of P-gp.     

Comparative pharmacokinetics of chlorogenic acid in beagles after oral administrations of single compound,the extracts of Lonicera japanica,and the mixture of chlorogenic acid,baicalin, and Forsythia suspense

Context: Chlorogenic acid (ChA) is the major compound in Shuang-Huang-Lian (SHL), which is mainly composed of ChA, baicalin, and Forsythia suspense Thunb Vahl.

Objective: The effects of co-existing compounds in SHL and Lonicera japanica Thunb on the absorption of ChA was investigated.

Materials and methods: According to 3?×?3 Latin-square test, ChA alone, the extracts of Lonicera japanica, or the mixture of ChA, baicalin and Forsythia suspense (ChA effective doses is 60?mg/kg) was separately given to six beagles for seven days. The oral pharmacokinetic parameters of ChA in plasma, urine and faeces were quantified by HPLC/UV and analyzed.

Results: The pharmacokinetic parameters of ChA alone, the extracts of Lonicera japanica, and the mixture of ChA, baicalin, and Forsythia suspense were as followed: C_max (2.350?±?0.483, 1.655?±?0.576, 2.332?±?0.606?μg/mL), AUC_0-∞ (6.324?±?1.853, 4.216?±?1.886, 6.074?±?1.473?μg·h/mL), t_1/2 (0.911?±?0.187, 1.204?±?0.309, 1.094?±?0.193?h), and T_max (1.861?±?0.499, 1.000?±?0.459, 1.833?±?0.279?h). Accumulative fraction excretion of ChA in urine were 0.73?±?0.55, 1.25?±?1.23, 1.05?±?0.96%, while that in faeces were 0.68?±?0.94, 0.19?±?0.40, and 1.76?±?3.57%.

Discussion and conclusion: Co-existing compounds in SHL have no effect on the absorption of ChA, while the concomitant compounds in Lonicera japanica could decrease that of ChA. ChA in Beagles might have high biological transformation.     

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.     

Epigallocatechin-3-gallate decreases the transport and metabolism of simvastatin in rats

1.?This study aimed to investigate the potential impact of epigallocatechin-3-gallate (EGCG) on the pharmacokinetic behaviors of simvastatin and its metabolite simvastatin acid and explored the possible role of metabolizing enzymes and transporters of this food–drug interaction.

2.?Female SD rats were intravenously administered with EGCG (5?mg/kg), ketoconazole (10?mg/kg) and rifampin (10?mg/kg), followed by intravenous administration of 2?mg/kg simvastatin. In vitro, the effects of EGCG on Cytochrome P450 enzymes (CYP450) and organic anion transporting polypeptides (OATPs) were studied using human hepatic microsomes and human embryonic kidney 293 (HEK293) cells overexpressing OATP1B1 or OATP1B3. The results showed that areas under concentration–time (AUC) curves of simvastatin and simvastatin acid increased by 2.21- and 1.4-fold while the clearance was reduced by 2.29- and 1.4-fold, respectively, when co-administered with EGCG. In vitro experiments suggested the inhibitory effect of EGCG on CYP enzymes (IC₅₀: 18.37?±?1.36?μM, 26.08?±?1.51?μM for simvastatin and simvastatin acid, respectively). Simvastatin transport by OATP1B1 and OATP1B3 was also inhibited by EGCG (IC₅₀: 8.68?±?1.27?μM and 22.67?±?1.42?μM, respectively).

3.?The presently reported novel food–drug interaction between EGCG and simvastatin involves the inhibition of not only CYP450 enzymes but also OATPs by EGCG.     

In vitro inhibition of UGT1A3, UGT1A4 by ursolic acid and oleanolic acid and drug–drug interaction risk prediction

1.?Ursolic acid (UA) and oleanolic acid (OA) may have important activity relevant to health and disease prevention. Thus, we studied the activity of UA and OA on UDP-glucuronosyltransferases (UGTs) and used trifluoperazine as a probe substrate to test UGT1A4 activity. Recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as a probe reaction for other UGT isoforms.

2.?UA and OA inhibited UGT1A3 and UGT1A4 activity but did not inhibit other tested UGT isoforms.

3.?UA-mediated inhibition of UGT1A3 catalyzed 4-MU-β-d-glucuronidation was via competitive inhibition (IC₅₀ 0.391?±?0.013?μM; K_i 0.185?±?0.015?μM). UA also competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC₅₀ 2.651?±?0.201?μM; K_i 1.334?±?0.146?μM).

4.?OA offered mixed inhibition of UGT1A3-mediated 4-MU-β-d-glucuronidation (IC₅₀ 0.336?±?0.013?μM; K_i 0.176?±?0.007?μM) and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC₅₀ 5.468?±?0.697?μM; K_i 6.298?±?0.891?μM).

5.?Co-administering OA or UA with drugs or products that are substrates of UGT1A3 or UGT1A4 may produce drug-mediated side effects.     

Interaction of isoflavonoids with human liver microsomal cytochromes P450: inhibition of CYP enzyme activities

1.?The possibility of interaction of isoflavonoids with concomitantly taken drugs to determined isoflavonoids safety was studied. Inhibition of nine forms of cytochrome P450 (CYP3A4, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2C9, CYP2D6 and CYP2E1) by 12 isoflavonoids (daidzein, genistein, biochanin A, formononetin, glycitein, equol and six glucosides, daidzin, puerarin, genistin, sissotrin, ononin and glycitin) was studied systematically.

2.?The most potent inhibitors were genistein and daidzein inhibiting noncompetitively the CYP2C9 with K_i of 35.95?±?6.96 and 60.56?±?3.53?μmol/l and CYP3A4 (inhibited by genistein with K_i of 23.25?±?5.85?μmol/l also by a noncompetitive mechanism). Potent inhibition of CYP3A4 was observed also with biochanin A (K_i of 57.69?±?2.36?μmol/l) and equol (K_i of 38.47?±?2.32?μmol/l).

3.?Genistein and daidzein inhibit noncompetitively CYP3A4 and CYP2C9. With plasma levels in micromolar range, a clinically important interaction with concomitantly taken drugs does not seem to be probable.     

Antioxidant capacity of Typha angustifolia extracts and two active flavonoids

Context: The pollen of Typha angustifolia L. (Typhaceae) has been used as a traditional Chinese medicine for improving the microcirculation and promoting wound healing. Flavonoids are the main constituent in the plant, but little is known about the antioxidant activity of the principal constituent of the pollen in detail.

Objectives: To assess the antioxidant activities of ethanol and water extracts and two constituents of the pollen.

Materials and methods: Plant material (1?g) was extracted by 95% ethanol and water (10?mL?×?2, 1?h each), respectively. The extracted activities (0.8–2.6?mg/mL) were measured by DPPH and the reducing activity of ferric chloride (1.7–2.6?mg/mL). Typhaneoside and isorhamnetin-3-O-neohesperidoside (I3ON) (2.8–70?μmol/L) were investigated on the relationship between NO, MDA and SOD in HUVECs treated with 100?μg/mL of LPS for 24?h.

Results: Nine compounds were identified by UPLC-MS. Ethanol extract showed IC₅₀ values in DPPH (39.51?±?0.72) and Fe³⁺ reducing activity (82.76?±?13.38), higher than the water extract (50.85?±?0.74) and (106.33?±?6.35), respectively. Typhaneoside and I3ON promoted cell proliferation at the respective concentration range of 2.8 to 70?μmol/L (p?p?p?p?Conclusions: The constituents from Typha angustifolia could be a novel therapeutic strategy for LPS-induced inflammation.     

Investigation on pharmacokinetics,tissue distribution and excretion of a novel platinum anticancer agent in rats by Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

Abstract

1.?DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague–Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method.

2.?The area under concentration–time curve AUC_0?t and AUC_0?∞ for platinum originating from DN604 at 10?mg/kg were 25.15?±?1.29 and 28.72?±?1.04?μg/hml, respectively. The mean residence time MRT was 36.59?±?6.65?h. The volume of distribution V_z was 11.42?±?2.49?l/kg and clearance CL was 0.18?±?0.01?l/h/kg. In addition, the elimination half-life T_1/2z was 44.83?±?9.75?h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120?h was 63.5%?±?7.7% for urine, but only 6.94%?±?0.11% for feces.

3.?The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development.     

Effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism

Context: Asiatic acid has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism.

Materials and methods: The pharmacokinetics of orally administered asiatic acid (20?mg/kg) with or without glycyrrhizin pretreatment (100?mg/kg/day for seven days) were investigated using a LC–MS method. Additionally, the Caco-2 cell transwell model and rat liver microsome incubation systems were used to investigate the potential mechanism of glycyrrhizin’s effects on the pharmacokinetics of asiatic acid.

Results: The results showed that the C_max (221.33?±?21.06 vs. 324.67?±?28.64?ng/mL), AUC_0–inf (496.12?±?109.31 vs. 749.15?±?163.95?μg·h/L) and the t_1/2 (1.21?±?0.27 vs. 2.04?±?0.32?h) of asiatic acid decreased significantly (p?p?Discussion and conclusions: In conclusion, these results indicated that glycyrrhizin could decrease the system exposure of asiatic acid, possibly by inducing the activity of P-gp or CYP450 enzyme.     

Determination of cepharanthine in rat plasma by LC–MS/MS and its application to a pharmacokinetic study

Context: Cepharanthine (CPA) has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the pharmacokinetic characteristics after oral or intravenous administration of CPA by using a sensitive and rapid LC–MS/MS method.

Materials and methods: A sensitive and rapid LC–MS/MS method was developed for the determination of CPA in Sprague–Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (1?mg/kg) and the oral group (10?mg/kg). Blood samples (250?μL) were collected at designated time points and determined using this method. The pharmacokinetic parameters were calculated.

Results: The calibration curve was linear within the range of 0.1–200?ng/mL (r?=?0.999) with the lower limit of quantification at 0.1?ng/mL. After 1?mg/kg intravenous injection, the concentration of CPA reached a maximum of 153.17?±?16.18?ng/mL and the t_1/2 was 6.76?±?1.21?h. After oral administration of 10?mg/kg of CPA, CPA was not readily absorbed and reached C_max 46.89?±?5.25?ng/mL at approximately 2.67?h. The t_1/2 was 11.02?±?1.32?h. The absolute bioavailability of CPA by oral route was 5.65?±?0.35%, and the bioavailability was poor.

Discussion and conclusions: The results indicate that the bioavailability of CPA was poor in rats, and further research should be conducted to investigate the reason for its poor bioavailability and address this problem.     

Selenium and rutin alone or in combination do not have stronger protective effects than their separate effects against cadmium-induced renal damage

Context: Selenium (Se) and rutin (RUT) are antioxidants that protect against tissue damage.

Objective: In this study, the separate and combine protective effects of RUT and Se against cadmium (Cd)-induced renal damage were evaluated in rats.

Materials and methods: Wistar rats were treated by gavage to RUT (30?mg/kg) or Se (0.15?ppm) or Cd (200?ppm) in drinking water alone or in combination (30?mg/kg RUT?+0.15?ppm Se?+?200?ppm Cd). Corn oil was used as vehicle (2?mL/kg). After a 5-week treatment period, rat kidneys were removed for biochemical assays and histopathological examination. Se and Cd levels were evaluated by flame atomic absorption spectrophotometry.

Results: The malondialdehyde and glutathione levels as well as superoxide dismutase and catalase activities in the Cd-treated animals were increased compared with control values (0.056?±?0.0003 versus 0.011?±?0.0005?μmol/mg; 0.005?±?0.0006 versus 0.00085?±?0.0002?μg/mg; 1.62?±?0.09 versus 0.48?±?0.12 units/mg; 650?±?25 versus 361.89?±?31?μmol H₂O₂/mg, respectively). Cd treatment was also associated with decreased renal Se concentration (4.19?±?0.92 versus 7.73?±?0.7?μg/g dry weight), increased alkaline phosphatase (0.07?±?0.0015 versus 0.033?±?0.0019 unit/mg), acid phosphatase (0.029?±?0.0021 versus 0.015?±?0.0016 unit/mg), and lactate dehydrogenase (0.032?±?0.004 versus 0.014?±?0.0027 unit/mg) activities, respectively, and with evidence of severe renal damage. The combination of RUT and Se or their separate effects prevented the Cd-induced oxidative renal damage. However, their combine effects do not have stronger effects than their separate effect against Cd-induced renal damage.

Discussion and conclusion: RUT and Se function as potent antioxidant in the protection of renal damage induced by Cd.     

Pharmacokinetic evaluation of β-caryophyllene alcohol in rats and beagle dogs

1.?β-caryophyllene alcohol (BCPA) has shown therapeutic promise in the treatment of asthma and inflammation with low toxicity. The aim of the current study was to report the pharmacokinetic profiles of BCPA in rats and dogs.

2.?Following intravenous administration, BCPA exhibited moderate volumes of distribution (V_z) ranging from 5.63 to 8.97?L/kg in rats and low V_z (2.89?±?1.12?L/kg) in dogs. Systemic plasma clearance was high in both species, resulting in a short elimination half-life ranging from 29.6 to 48.3?min. In rats, the intravenous pharmacokinetics was dose dependent. The measured oral bioavailability was low in rats for BCPA solution (1.17?±?0.78%), suspension (1.21?±?0.33%) and PEG formulation (6.22?±?2.63%). The bioavailability was lower in dogs for BCPA solution (0.12?±?0.05%) and PEG formulation (0.25?±?0.07%), indicating significant species difference. However, treatment of plasma samples with β-glucuronidase increased the systematic exposure of BCPA as assessed from AUC _(0-∞) by 24.7- or 2.62-fold in rats and dogs, respectively, which suggested glucuronidation was a significant metabolic pathway for BCPA possibly due to first-pass metabolism.

3.?In summary, this was the first preclinical pharmacokinetic investigation of BCPA in animals, providing vital knowledge for further preclinical research and subsequent clinical trials.     

Influence of grapefruit juice on pharmacokinetics of triptolide in rats grapefruit juice on the effects of triptolide

1.?Triptolide, a major pharmacological component isolated from Tripterygium wilfordii Hook F (TWHF), is a substrate of both CYP3A4 and P-glycoprotein (P-gp).

2.?This study investigates the effects of GFJ on the pharmacokinetics of triptolide in rats.

3.?The pharmacokinetics of orally administered triptolide with or without GFJ pretreatment were investigated. A mechanistic study was also undertaken using the Caco-2 cell transwell model and rat liver microsomes incubation systems to support the in vivo pharmacokinetic data.

4.?The results indicated that coadministration of GFJ could increase the systemic exposure of triptolide significantly, including area under the curve (828.58?±?79.72 versus 541.53?±?45.23?ng·h/mL) and maximum plasma concentration (273.58?±?27.98 versus 193.67?±?10.08?ng/mL). The apparent permeability of triptolide across the Caco-2 cell transwell model increased significantly with the pretreatment of GFJ (from 1.62?±?0.25?×?10^?6 to 2.51?±?0.41?×?10^?6 cm/s), and the metabolic stability of triptolide was also increased from 32.6?±?5.1 to 52.5?±?7.8?min with the pretreatment of GFJ, and the difference was significant (p?5.?In conclusion, GFJ could increase the systemic exposure of triptolide in rats, when GFJ and triptolide was coadministered, and it might work mainly through increasing the absorption of triptolide by inhibiting P-gp, or through slowing down the metabolism of triptolide in rat liver by inhibiting the activity of CYP3A4.     

Pharmacokinetic interaction of aconitine,liquiritin and 6-gingerol in a traditional Chinese herbal formula,Sini Decoction

1.?This study aimed to investigate the pharmacokinetic interaction of the three ingredients in a traditional Chinese herbal formulation, Sini Decoction, and provide evidence for its compatibility mechanism.

2.?First, the effect of liquiritin and 6-gingerol on the pharmacokinetic parameters of aconitine was investigated in rats by using a sensitive and reliable LC–MS/MS method. Then the Caco-2 cell monolayer model and Rhodamine-123 uptake assay were used to investigate the effect of liquiritin and 6-gingerol on the absorption of aconitine and the activity of P-gp.

3.?The C_max of aconitine increased significantly (p?C_max and AUC_(0–t) of aconitine increased approximately twofold, and while t_1/2 only increased 1.2-fold. The Caco-2 cell monolayer model and Rhodamine-123 uptake assay indicated that both liquiritin and 6-gingerol could increase the absorption of aconitine by inhibiting the activity of P-gp.

4.?These results indicated that both liquiritin and 6-gingerol could promote the absorption of aconitine and increase its drug concentration in blood by inhibiting the activity of P-gp, and it could also provide evidence for compatibility mechanism of the traditional Chinese herbal formula, Sini Decoction.     

Calculation of AQCmax: comparison of five ophthalmic fluoroquinolone solutions

ABSTRACT

Objective: Ocular tissue penetration of five different ophthalmic fluoroquinolone solutions in the rabbit eye was measured and evaluated by an index of the maximum aqueous concentration (AQCmax).

Methods: Moxifloxacin 0.5% (MFLX), levofloxacin 0.5% (LVFX), gatifloxacin 0.3% (GFLX), ofloxacin 0.3% (OFLX), or tosufloxacin tosilate 0.3% (TFLX) were instilled into the eyes of white rabbits every 15?min for a total of three doses. Aqueous humor, cornea, iris/ciliary body and vitreous body were collected 10 to 240?min after instillation and drug concentrations were measured by high-performance liquid chromatography.

Results: The concentration of MFLX was the highest in each tissue, with maximum concentrations of MFLX in the aqueous humor (10.16?±?1.59?µg/mL) at 30?min after instillation, cornea (156.07?±?95.97?µg/g) and iris/ciliary body (11.92?±?4.00?µg/g) at 10?min after instillation, and vitreous body (0.099?±?0.033?µg/mL) at 30?min after instillation. The concentration of TFLX was the lowest in each tissue, with LVFX, GFLX, and OFLX sharing the mid-ranks. AQCmax?:?MIC₉₀ ratio for S.?aureus was 150.67 for MFLX, 10.6 for LVFX, 9.69 for GFLX, 3.48 for OFLX, and could not be determined for TFLX.

Conclusion: AQCmax is a useful pharmacokinetic parameter for determining the therapeutic efficacy of an ophthalmic antibiotic, especially when combined with MIC₉₀ values for intraocular pathogens. C_max of MFLX ophthalmic solution was superior in all tissues (cornea, aqueous humor, iris/ciliary body and vitreous body) among the five ophthalmic solutions studied, exceeding the MIC₉₀ of S.?aureus in all tissues, and MIC₉₀s of S.?epidermidis, B.?cereus, and P.?acnes in aqueous humor, cornea, and iris/ciliary body. AQCmax was approximately proportional to C_max in iris/ciliary body and vitreous, and may be used in combination with MIC₉₀s as an index to predict the most appropriate dose and frequency of ophthalmic antibiotics in conjunction with other PK/PD parameters. This study may provide the groundwork for calculation of AQCmax in humans.     

Influence of andrographolide on the pharmacokinetics of warfarin in rats

Context: Andrographolide and warfarin are often used together in clinics in China. However, the herb-drug interaction between andrographolide and warfarin is still unknown.

Objective: This study investigates the herb-drug interaction between andrographolide and warfarin in vivo and in vitro.

Materials and methods: A sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in male Sprague-Dawley rats plasma, and then the pharmacokinetics of orally administered warfarin (0.5?mg/kg) with or without andrographolide (30?mg/kg/day for 7?days) pretreatment was investigated. In addition, Sprague-Dawley rat liver microsomes incubation systems were used to support the in vivo pharmacokinetic data and investigate its potential mechanism.

Results: The method validation results showed that a sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in rat plasma samples. The pharmacokinetic results indicated that co-administration of andrographolide could increase the systemic exposure of warfarin significantly, including area under the curve (118.92?±?18.08 vs. 60.58?±?9.46?μg?×?h/mL), maximum plasma concentration (3.32?±?0.41 vs. 2.35?±?0.25?μg/mL) and t_1/2 (22.73?±?3.28 vs. 14.27?±?2.67?h). Additionally, the metabolic stability of warfarin increased from 23.5?±?4.7 to 38.7?±?6.1?min with the pretreatment of andrographolide, and the difference was significant (p?Discussion and conclusion: In conclusion, andrographolide could increase the systemic exposure of warfarin in rats when andrographolide and warfarin were co-administered, and possibly by slowing down the metabolism of warfarin in rat liver by inhibiting the activity of CYP3A4 or CYP2C9.