Single-dose Pharmacokinetic Study Research Articles

Pharmacokinetic study and bioavailability of a novel synthetic trioxane antimalarial compound 97/63 in rats.

Single dose pharmacokinetics study of 97/63 (IND191710, 2004), a trioxane antimalarial developed by Central Drug Research Institute, Lucknow, India, was studied in rats following intravenous and oral administration. Serum samples were analysed by HPLC-UV assay. Separation was achieved on a RP-18 column attached with a guard using acetonitrile : phosphate buffer (70 : 30% v/v) with UV detector at wavelength 244 nm. Serum samples were extracted with n-hexane. Two-compartment model without lag time and first-order elimination rate was considered to be the best fit to explain the generated oral and intravenous data. Method was sensitive with limit of quantification of 10 ng mL−1. Recovery was >74%. Terminal half-life and area under curve (AUC) after administering single oral (72 mg kg−1) and intravenous (18 mg kg−1) doses were 10.61 h, 10.57 h, and 1268.97 ng h mL−1, 2025.75 ng h mL−1, respectively. After oral dose, 97/63 was rapidly absorbed attaining maximum concentration 229.24 ng mL−1 at 1 h. Bioavailability of 97/63 was ~16%. The lower bioavailability of drug may be due to poor solubility and first-pass metabolism and can be improved by prodrug formation of 97/63.

Preparation and in vitro/in vivo evaluation of esomeprazole magnesium-modified release pellets

To reduce the drug plasma concentration fluctuation without being destroyed by gastric fluid, novel Esomeprazole magnesium modified-release pellets (EMZ-MRPs) with suitable in vitro release profiles and good in vitro and in vivo correlation (IVIVC) were developed. Fluid-bed was used to obtain EMZ-loaded pellets by spraying drug suspension onto blank sugar pellets. The drug-loaded pellets were subsequently coated with Eudragit® RS30D/RL30D (ERS/ERL) aqueous dispersion to achieve sustained-release (SR) characteristics. Furthermore, the SR pellets were coated with Eudragit® L30D-55 (EL-55) aqueous dispersion to achieve enteric properties. Besides, isolated coating film was necessary between drug layer and SR layer, as well as SR and enteric-coated layer to protect from their possible reaction. The resulting pellets were filled into the hard gelatin capsules for in vitro release processing and single-dose pharmacokinetic study in rats. The optimal formulation achieved good SR feature both in vitro and in vivo with a relative bioavailability of 103.50%. A good IVIVC was characterized by a high coefficient of determination (r = 0.9945) by deconvolution method. Compared to those of EMZ enteric-coated pellets (EMZ-ECPs, trade name NEXIUM), the in vivo study make known that the EMZ-MRPs with decreased maximum plasma concentration (Cmax), prolonged peak concentration time (Tmax) and mean residence time (MRT), and similar values both area under concentration–time curve from 0 to t (AUC0–t) and 0 to infinity (AUC0–∞). Collectively, these results manifested EMZ-MRPs had a satisfactory sustained-release behavior, a desired pharmacokinetic property, improved in vivo retention and decreased plasma drug concentration fluctuation.

Pharmacokinetic drug interactions between apigenin, rutin and paclitaxel mediated by P-glycoprotein in rats.

The aim of present study was to investigate the effects of apigenin and rutin on the pharmacokinetics of paclitaxel after oral administration of paclitaxel with apigenin and rutin to rats. Paclitaxel (40 mg/kg) was administered orally alone and in combination with apigenin and rutin (10, 20, and 40 mg/kg) for 15 consecutive days. In the single-dose pharmacokinetic study (SDS), blood samples were collected on 1st day whereas on 15th day in the multiple-dose pharmacokinetic study (MDS). The plasma concentrations of paclitaxel were increased dose-dependently in the combination of apigenin and rutin compared to that of paclitaxel control in SDS and MDS (p < 0.01). The areas under the plasma concentration-time curve (AUC) and the plasma peak concentrations (C max) of paclitaxel with apigenin and rutin were significantly higher (p < 0.01) than that of the control. The AUCs and C max of paclitaxel were increased with apigenin and rutin in the dose-dependent manner. The half-life (t 1/2) was significantly longer than that of the control. Non-everted sacs were filled with paclitaxel 100 μM in the presence and absence of verapamil (50 μM), apigenin, and rutin (50, 100 μM) and incubated at 37 ºC for 60 min. The absorption of paclitaxel was increased in the presence of apigenin, rutin, and verapamil, a typical P-glycoprotein and Cyp3A4 inhibitor. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with apigenin and rutin.

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

BackgroundDose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients. We propose a simulation-based dose-selection method for PK studies of hemodialysis patients using a subpharmacological dose of oseltamivir as a model drug.MethodsThe concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured by liquid chromatography-tandem mass spectrometry. To determine a low oseltamivir dose exhibiting PK linearity, a pilot low dose determination investigation (n = 4) was performed using a single administration dose-escalation study. After the dose was determined, a low dose study (n = 10) was performed, and the optimal dose required to reach the hypothetical target OC exposure (area under the concentration-time curve [AUC] of 60,000 ng · hr/mL) was simulated using a nonparametric superposition method. Finally, observed PKs at the optimal dose were compared to the simulated PKs to verify PK predictability.ResultsIn the pilot low dose determination study, 2.5 mg of oseltamivir was determined to be the low dose. Subsequently, we performed a single-dose PK study with the low oseltamivir dose in an additional group of 10 hemodialysis patients. The predicted AUClast of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUClast of OC. The observed PK profiles of OC at a 35-mg oseltamivir dose and the simulated data based on the low dose study were in close alignment.ConclusionThe results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients.

LC–Q-TOF-MS/MS determination of darunavir and its metabolites in rat serum and urine: Application to pharmacokinetics

A simple, rapid and reliable liquid chromatography coupled with quadrupole time of flight mass spectrometry (LC–Q-TOF-MS/MS) method was developed and validated for simultaneous determination of darunavir and its metabolites in rat serum and urine. The separation was accomplished on an Agilent RP-18 (250×4.6mm, 5μm) column using 20mM ammonium acetate and methanol (40:60, v/v) as a mobile phase at a flow rate of 1.0mL/min in an isocratic mode. The [M+H]+ ions of darunavir (m/z 548) and metabolites-I (m/z 392) were monitored in positive mode of ionization, while [M−H]− ion of metabolite-II (m/z 172) in negative mode selectively. The matrix effects of rat serum and urine were found to be negligible and the recoveries were 87–93% for all the analytes. The short and long term stability of darunavir and its metabolites was within acceptable limits and the lower limits of quantification were in the range of 3.63–5.24ng/mL with a linear range of 5–5000ng/mL in rat serum as well as urine. The method exhibited good intra- and inter-day performance in terms of 2.54–8.92% precision and 0–5% accuracy. The method was successfully applied to a single-dose pharmacokinetic study of darunavir boosted with ritonavir in Wistar rats.

Preparation and IVIVC evaluation of salvianolic acid B micro-porous osmotic pump pellets

Purpose: Salvianolic acid B micro-porous osmotic pump controlled release pellets (SalB-CRPs) with suitable in vitro release profiles and good in vitro and in vivo correlation (IVIVC) were developed.Method: Extrusion-spheronization was used to prepare the starter cores containing SalB/MCC/Kollidon®CL-SF/Flowlac®100 of 30:40:15:15 [w/w, The formulation composition of SalB immediate-release pellets (SalB-IRPs)] and complexed with lactose. The pellets were subsequently coated with Surelease aqueous dispersion to achieve controlled-release properties. Furthermore, a single-dose pharmacokinetics study was carried out in New Zealand White (NZW) rabbits.Results: In the starter cores, the lactose content was 25% based on the SalB-IRPs constituent. The optimal coating polymer ratio of Surelease aqueous dispersion and polyvinyl alcohol–polyethylene glycol (PVA–PEG) graft copolymer (EC/PVA–PEG) was found to be 70:30 (w/w, %) with a coating weight of 5%. The prepared SalB-CRPs had similar in vitro release under three different pH release mediums. A good IVIVC was characterized by a high coefficient of determination (r = 0.9801). The in vivo study indicated that the maximum plasma concentration (Cmax) of SalB-CRPs was decreased, peak concentration time (Tmax) and mean residence time (MRT) were all prolonged, as that of SalB-IRPs. In addition, the area under concentration–time curve from 0 to 24 h (AUC0–24 h) and 0 to infinity (AUC0–∞) were significantly higher, compared with those of SalB-IRPs.Conclusion: Collectively, these results manifested that SalB-CRPs were likely to be a more suitable formulation in treating cardiovascular disease with improved in vivo retention, decreased plasma drug concentration fluctuation.

Pharmacokinetics of Pilsicainide Hydrochloride for Injection in Healthy Chinese Volunteers: A Randomized, Parallel-Group, Open-Label, Single-Dose Study

BackgroundPilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation. ObjectiveThe objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride. MethodsThis Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration–time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs. ResultsThirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m2) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean Cmax was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) μg/mL, respectively; AUC0–24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h · μg/mL; and AUC0–∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h · μg/mL. The ranges for t½z, CL, and Vz were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC0–24 values in the 0.50-mg/kg dose group (P = 0.044), and Vz showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters. ConclusionsPilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC0–24 and AUC0–∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546.

Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression

Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300mg/kg/day with repeated dosing from postpartum day (PPD) 8 to PPD 35/36. In-life, clinical pathology, anatomic pathology, and toxicokinetics evaluations were performed. In Study 2, single oral doses of aliskiren (0, 100 or 300mg/kg) were given to 14-, 21-, 24-, 28-, 31- or 36-day-old rats; in-life data and toxicokinetics were evaluated. Study 3 was a single dose (3mg/kg i.v.) pharmacokinetic study in juvenile rats on PPD 8, 14, 21 and 28. In Study 4, naïve rats were used to investigate ontogenic changes of the multidrug-resistant protein 1 (MDR1) and the organic anion transporting polypeptide (OATP) mRNA in several organs. Oral administration of aliskiren at 100 and 300mg/kg caused unexpected mortality and severe morbidity in 8-day-old rats. Aliskiren plasma and tissue concentrations were increased in rats aged 21days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. In conclusion, severe toxicity and increased exposure in very young rats after oral administration of aliskiren are considered to be the result of immature drug transporter systems. Immaturity of MDR1 in enterocytes appears to be the most important mechanism responsible for the high exposure.

Zinc Oxide Nanoparticles Show Antidiabetic Activity in Streptozotocin-Induced Type 1 and 2 Diabetic Rats

The correlation of diabetes and an imbalance in zinc homeostasis makes zinc-based therapy an attractive proposition. In this study, zinc oxide nanoparticles were evaluated for antidiabetic effects and safety. Zinc oxide nanoparticles (1, 3 and 10 mg/kg) were tested for antidiabetic activity in streptozotocin-induced Type 1 and 2 diabetic rats. A single-dose pharmacokinetic study, cytotoxicity, hemolysis, acute and subacute toxicity tests, and mechanism-of-action studies were performed. Oral administration of zinc oxide nanoparticles resulted in significant antidiabetic effects--that is, improved glucose tolerance, higher serum insulin (70%), reduced blood glucose (29%), reduced nonesterified fatty acids (40%) and reduced triglycerides (48%). Nanoparticles were systemically absorbed resulting in elevated zinc levels in the liver, adipose tissue and pancreas. Increased insulin secretion and superoxide dismutase activity were also seen in rat insulinoma (RIN-5F) cells. Nanoparticles were safe up to a 300 mg/kg dose in rats. Zinc oxide nanoparticles are a promising antidiabetic agent warranting further studies.

Moxifloxacin Pharmacokinetics and Pleural Fluid Penetration in Patients with Pleural Effusion

The aim of this study was to evaluate the pharmacokinetics and penetration of moxifloxacin (MXF) in patients with various types of pleural effusion. Twelve patients with empyema/parapneumonic effusion (PPE) and 12 patients with malignant pleural effusion were enrolled in the study. A single-dose pharmacokinetic study was performed after intravenous administration of 400 mg MXF. Serial plasma (PL) and pleural fluid (PF) samples were collected during a 24-h time interval after drug administration. The MXF concentration in PL and PF was determined by high-performance liquid chromatography, and main pharmacokinetic parameters were estimated. Penetration of MXF in PF was determined by the ratio of the area under the concentration-time curve from time zero to 24 h (AUC24) in PF (AUC24PF) to the AUC24 in PL. No statistically significant differences in the pharmacokinetics in PL were observed between the two groups, despite the large interindividual variability in the volume of distribution, clearance, and elimination half-life. The maximum concentration in PF (CmaxPF) in patients with empyema/PPE was 2.23±1.31 mg/liter, and it was detected 7.50±2.39 h after the initiation of the infusion. In patients with malignant effusion, CmaxPF was 2.96±1.45 mg/liter, but it was observed significantly earlier, at 3.58±1.38 h (P<0.001). Both groups revealed similar values of AUC24PF (31.83±23.52 versus 32.81±12.66 mg·h/liter). Penetration of MXF into PF was similarly good in both patient groups (1.11±0.74 versus 1.17±0.39). Despite similar plasma pharmacokinetics, patients with empyema/parapneumonic effusion showed a significant delay in achievement of PF maximum MXF levels compared to those with malignant effusion. However, in both groups, the degree of MXF PF penetration and the on-site drug exposure, expressed by AUC24PF, did not differ according to the type of pleural effusion.

Determination of 20(S)-protopanaxadiol in human plasma by HPLC–MS/MS: Application to a pharmacokinetic study

A rapid, specific and sensitive HPLC–MS/MS method was developed and validated for the determination of 20(S)-protopanaxadiol (PPD) in human plasma. PPD and the internal standard PD were extracted from plasma by liquid–liquid extraction with cyclohexane–methylene dichloride (2:1, v/v). The separation was performed on a HyPURIYTY C18 column using methanol–5mM ammonium formate (90:10, v/v) as mobile phase at a flow rate of 0.35mL/min. Mass spectrometric detection was carried out by electrospray ionization (ESI) in the positive ion mode using multiple reaction monitoring (MRM). The monitored transitions were m/z 425.4→217.2 for PPD and at m/z 461.4→425.5 for PD. The method was linear over the range 0.512–100ng/mL with a lower limit of quantification (LLOQ) of 0.512ng/mL. The mean extraction recovery of PPD was greater than 78.2% and no significant matrix effect was detected. The intra- and inter-day precisions were less than 10% and the biases below 4% for PPD. The validated method was applied to a three-level single-dose clinical pharmacokinetics study of 12 healthy Chinese volunteers and the main pharmacokinetic parameters of PPD were obtained.

Human pharmacokinetics of xanthohumol, an antihyperglycemic flavonoid from hops

Xanthohumol (XN) is a bioactive prenylflavonoid from hops. A single-dose pharmacokinetic (PK) study was conducted in men (n = 24) and women (n = 24) to determine dose-concentration relationships. Subjects received a single oral dose of 20, 60, or 180 mg XN. Blood was collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 h. Plasma levels of XN and its metabolites, isoxanthohumol (IX), 8-prenylnaringenin (8PN), and 6-prenylnaringenin (6PN) were measured by LC-MS/MS. Xanthohumol (XN) and IX conjugates were dominant circulating flavonoids among all subjects. Levels of 8PN and 6PN were undetectable in most subjects. The XN PK profile showed peak concentrations around 1 h and between 4-5 h after ingestion. The maximum XN concentrations (C(max)) were 33 ± 7 mg/L, 48 ± 11 mg/L, and 120 ± 24 mg/L for the 20, 60, and 180 mg dose, respectively. Using noncompartmental modeling, the area under the curves (AUC(0→∞)) for XN were 92 ± 68 h × μg/L, 323 ± 160 h × μg/L, and 863 ± 388 h × μg/L for the 20, 60, and 180 mg dose, respectively. The mean half-life of XN was 20 h for the 60 and 18 h for the 180 mg dose. XN has a distinct biphasic absorption pattern with XN and IX conjugates being the major circulating metabolites.

Bioavailability, bioequivalence, and in vitro-in vivo correlation of oxybutynin transdermal patch in rabbits.

The first objective of the proposed research work includes comparative bioavailability and bioequivalence evaluation of oxybutynin transdermal patch with respect to different permeation enhancers. The second objective was to evaluate different in vitro methods along with synthetic membranes toward development of an in vitro-in vivo correlation. Oleic acid (fatty acid), Soluphor P (2-pyrrolidone, cosolvent), menthol (volatile oil), and dipropylene glycol (plasticizer) were selected as representatives from different classes of permeation enhancers. A random, crossover, single-dose pharmacokinetic study was carried out on male New Zealand white rabbits to determine bioavailability and bioequivalence. The obtained pharmacokinetic data were correlated with in vitro drug release using convolution-deconvolution approach. All developed formulations were found to be bioequivalent with respect to the marketed patch (Oxytrol®) on the basis of level of C max, AUC0-96, and AUCtotal (0.8-1.25). A biphasic linear correlation was obtained pertaining to differential diffusion behavior of the drug in vivo during the experimental timeframe. Because of close resemblance to skin, Cuprophan® membrane was found to be more suitable for developing an IVIVC than Millipore® membrane.

A simple pharmacokinetic model of alendronate developed using plasma concentration and urine excretion data from healthy men

The study of pharmacokinetics of alendronate has been hampered by difficulties in accurately and reproducibly determining their concentrations in serum and urine. Thus, pharmacokinetic characteristics of alendronate have been described in many reports based on urinary excretion data; and plasma pharmacokinetics and the simultaneous pharmacokinetic models of alendronate in plasma and urine are not available. The aims of this study were to measure alendronate concentration in plasma and excretion in urine concurrently and to develop compartmental pharmacokinetic model using urine data. In open-label, single-dose pharmacokinetic study, 10 healthy male volunteers received oral dose of alendronate (70 mg tablet). Blood and urine alendronate concentrations were determined using validated high-performance liquid chromatography method. Non-compartmental analysis was performed using WinNonlin program (Pharsight Inc., Apex, NC). A one-compartment pharmacokinetic model was applied to describe pharmacokinetics of alendronate. A peak plasma alendronate concentration of 33.10 ± 14.32 ng/mL was attained after 1.00 ± 0.16 h. The cumulative amount of alendronate excreted in urine and peak excretion rate were 731.28 ± 654.57 μg and 314.68 ± 395.43 μg/h, respectively. The model, which included first-order absorption rate for oral dosing, showed good fit to alendronate data obtained from plasma and urine. The absorption rate constant was 2.68 ± 0.95 h–1. The elimination rate constants Kurine and Knon-ur were 0.005 ± 0.004 h−1 and 0.42 ± 0.08 h−1, respectively. The pharmacokinetics of alendronate in plasma and urine of healthy men can be predicted using one-compartment model, and thus the behavior of drug in plasma can be estimated from urinary excretion data.

Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacs in vitro

The aim of this study was to investigate the effect of naringenin on the pharmacokinetics (PK) of felodipine in rats and membrane permeability across rat everted gut sacs in vitro. Rats were simultaneously co-administered with felodipine 10 mg/kg, p.o. and naringenin (25, 50 and 100 mg/kg, p.o.) for 15 consecutive days. Rats of the control groups received the corresponding volume of vehicle. Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS). The PK parameters were calculated using Thermo kinetica. The co-administration of naringenin significantly elevated the Cmax and increased the AUCtotal of felodipine in dose-dependent manner. The Cmax of felodipine was increased from 173.25 ± 14.65 to 275.61 ± 44.62 and 223.26 ± 26.35 to 561.32 ± 62.53 ng/mL in SDS and MDS, respectively, at the dose of naringenin 100 mg/kg. The AUCtotal of felodipine was significantly (p < 0.001) increased from 2050.48 ± 60.57 to 3650.22 ± 78.61 and 3276.51 ± 325.61 to 7265.25 ± 536.11 (ng/mL/h) in SDS and MDS, respectively. The permeability of felodipine was increased in presence of naringenin and ritonavir (standard P-glycoprotein (P-gp) and Cytochrome P450 (CYP)3A4 inhibitor). Felodipine is a substrate of CYP3A4, and naringenin was reported to be a modulator of P-gp and CYP3A4. These results suggest that naringenin significantly increased the Cmax and AUC of felodipine is due to P-gp and CYP3A4 inhibition.

Evaluation of First-Pass Cytochrome P4503A (CYP3A) and P-glycoprotein Activities Using Felodipine and Hesperetin in Combination in Wistar Rats and Everted Rat Gut Sacs in Vitro

The effects of hesperetin on the pharmacokinetics and the role of P-glycoprotein (P-gp) in the transport of felodipine were investigated in rats and in vitro. Felodipine was administered orally (10 mg/kg) without or with hesperetin (25, 50 and 100 mg/kg) to rats for 15 consecutive days. Blood samples were collected at different time intervals on 1(st) day in single dose pharmacokinetic study (SDS) and on 15(th) day in multiple dose pharmacokinetic study (MDS). The area under the plasma concentration-time curve (AUC0-∞ ) and the peak plasma concentration (Cmax ) of felodipine were dose-dependently increased in SDS and MDS with hesperetin compared to control ( p < 0.001). The half-life (t1/2 ) and mean residence time was longer than the control group in both studies. The role of P-gp determined using everted rat gut sacs in vitro by incubating felodipine with or without hesperetin and verapamil (typical P-gp and CYP3A4 inhibitor). The in vitro experiments revealed that the verapamil and hesperetin increased the intestinal absorption of felodipine (p < 0.01). Concurrent use of hesperetin dramatically altered the pharmacokinetics of felodipine leading to an increase in systemic exposure. The likely mechanism is inhibition of CYP3A4-mediated first-pass metabolism and P-gp in the intestine and the liver.

Pharmacokinetic and In Vivo Efficacy Studies of the Mycobactin Biosynthesis Inhibitor Salicyl-AMS in Mice

Mycobactin biosynthesis in Mycobacterium tuberculosis facilitates iron acquisition, which is required for growth and virulence. The mycobactin biosynthesis inhibitor salicyl-AMS [5'-O-(N-salicylsulfamoyl)adenosine] inhibits M. tuberculosis growth in vitro under iron-limited conditions. Here, we conducted a single-dose pharmacokinetic study and a monotherapy study of salicyl-AMS with mice. Intraperitoneal injection yielded much better pharmacokinetic parameter values than oral administration did. Monotherapy of salicyl-AMS at 5.6 or 16.7 mg/kg significantly inhibited M. tuberculosis growth in the mouse lung, providing the first in vivo proof of concept for this novel antibacterial strategy.

Systemic and brain bioavailabilities of d-Phenylglycine-l-Dopa, a sustained dopamine-releasing prodrug

d-Phenylglycine-l-Dopa (d-PhG-l-Dopa), designed as a dipeptide mimetic prodrug of dopamine, has been proven to have 31-fold higher oral bioavailability than l-Dopa in rats. To further investigate if this dipeptide enters the brain, a single-dose pharmacokinetic study by i.v. administration, in comparison with l-Dopa, was conducted to monitor brain availability. The dopamine level in the brain was also determined. The results indicated that both d-PhG-l-Dopa and l-Dopa entered the brain rapidly (Tmax 1 minute) with similar degrees of penetration (AUCbrain/AUCplasma 8.83% vs. 7.61%). As d-PhG-l-Dopa had higher systemic exposure than l-Dopa (AUCplasma 23.79 μmol*min/mL vs. 12.09 μmol*min/mL), it thus had higher brain availability (AUCbrain 2.0 μmol*min/mL vs. 0.92 μmol*min/mL). Although the AUCbrain dopamine after d-PhG-l-Dopa treatment was only 24% of that from l-Dopa treatment, it however exhibited higher anti-Parkinsonism activity than l-Dopa (reduction in rotation number 47.9 ± 5.5% vs. 27.3 ± 4.8%). Higher brain dopamine residual properties of d-PhG-l-Dopa treatment compared to l-Dopa treatment, namely 3.2 times longer MRTbrain dopamine (172.15 vs. 53.78 minutes), 10 times longer Tmax brain dopamine (30 vs. 3 minutes) and 8.36 times longer half-life (T1/2Tmaxtoend(min) 112.51 vs. 13.46 minutes), may explain the result. Moreover, the long terminal half-life of brain dopamine upon d-PhG-l-Dopa treatment indicated its slow dopamine-releasing property compared with l-Dopa treatment (112.51 vs. 44.85 minutes). It is also important to note that brain dopamine level was better controlled in the d-PhG-l-Dopa group than in the l-Dopa group (Cmax/Cmin 1.62 vs. 9.85). In conclusion, this study demonstrated that d-PhG-l-Dopa is an intrinsic dopamine-sustained-releasing prodrug. The limited concentration fluctuation of released dopamine in the brain is beneficial for the clinical management of Parkinson's disease.

Influence of CYP2C8*2 on the Pharmacokinetics of Pioglitazone in Healthy African-American Volunteers

To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers. Prospective, open-label, single-dose pharmacokinetic study. University of Colorado Hospital Clinical and Translational Research Center. Healthy African-American volunteers between 21 and 60years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (9 participants), CYP2C8*1/*2 (7 participants), and CYP2C8*2/*2 (1 participant). Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study. Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8*1/*1 genotype and CYP2C8*2 carriers. Pioglitazone area under the plasma concentration-time curve (AUC)0-∞ and half-life (t1/2 ) did not differ significantly between CYP2C8*1/*1 and CYP2C8*2 carriers (AUC0-∞ 7331±2846 vs 10431±5090ng*h/ml, p=0.15, t1/2 7.4±2.7 vs 10.5±4.0h, p=0.07). M-III and M-IV AUC0-48 also did not differ significantly between genotype groups. However, the M-III:pioglitazone AUC0-48 ratio was significantly lower in CYP2C8*2 carriers than CYP2C8*1 homozygotes (0.70±0.15 vs 1.2±0.37, p=0.006). Similarly, CYP2C8*2 carriers had a significantly lower M-III:M-IV AUC0-48 ratio than participants with the CYP2C8*1/*1 genotype (0.82±0.26 vs 1.22±0.26, p=0.006). These data suggest that CYP2C8*2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC0-48 ratio of M-III:parent drug, and the AUC0-48 ratio of M-III:M-IV. Larger studies are needed to further investigate the impact of CYP2C8*2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.

A clinical pharmacokinetic study comparing two azelastine hydrochloride nasal formulations in a single-dose design

Azelastine hydrochloride is a potent second-generation antihistamine, available in Europe and the USA as a nasal spray formulation for the treatment of allergic rhinitis symptoms. GlaxoSmithKline (GSK) Consumer Healthcare has developed a new nasal formulation of azelastine hydrochloride. The present study was aimed at comparing the clinical pharmacokinetic profiles and assessing the bioequivalence of the new formulation of azelastine hydrochloride with a marketed reference nasal spray product. This was a randomized, two-way crossover, two-stage, single-dose pharmacokinetic study with 2 weeks washout between the two treatment periods. A dosage of 0.28 mg of the test and reference products was administered as a single dose to healthy volunteers according to the crossover design. Twenty-three subjects (15 subjects from stage 1 and 8 subjects from stage 2) were enrolled in the study. Adjusted mean values for AUC0-t were 1,526.8 h pg/mL for the test drug and 1,441.5 h pg/mL for the reference drug; for C max the values were 61.59 pg/mL for the test drug and 58.21 pg/mL for the reference drug. The 94.12 % CI of geometric mean ratios (test/reference) were 0.99-1.13 and 0.95-1.18 for AUC0-t and C max. This met the predefined criteria for bioequivalence between test and reference drugs. Secondary pharmacokinetic parameters for azelastine and for the metabolite desmethyl azelastine, AUC(0-∞) and t max, were numerically similar between the two study treatments. Both test and reference azelastine hydrochloride formulations were well tolerated at single dose. This study demonstrated the bioequivalence between the new azelastine hydrochloride nasal spray formulation and the marketed reference Allergodil(®) after single-dose administration.