Comprehensive stability analysis of 13 ß-lactams and ß-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation.

Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain ß-lactams (e.g., imipenem) and ß-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 ß-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at -20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on ß-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of ß-lactamase-related degradation.

Combined phototherapy with metabolic reprogramming-targeted albumin nanoparticles for treating breast cancer.

Triple-negative breast cancer (TNBC) is characterized by rapid tumor growth and resistance to cancer therapy, and has a poor prognosis. Accumulating data have revealed that cancer metabolism relies on both the Warburg effect and oxidative phosphorylation (OXPHOS), which are strongly related to the high proliferation and chemoresistance of cancer cells. Phototherapy is considered as a non-invasive method to precisely control drug activity with reduced side effects. Herein, our group introduced an Abraxane-like nanoplatform, named LCIR NPs, which significantly eradicates cancer cells via synergism between metabolic reprogramming and phototherapy effects. Endowed with mitochondria-targeting residues, the nanoparticles efficiently inhibited mitochondrial complexes I and IV as well as hexokinase II, leading to the depletion of intracellular ATP. Consequently, the photodynamic and photothermal effect triggered by NIR irradiation was enhanced due to the alleviation of hypoxia and the thermoresistance mechanism that rely on mitochondrial metabolism. In vivo experiments showed that the tumor size of mice that received the combination treatment was only 50.7 mm3, which was 21 times smaller than that of the untreated group and was much lower than those of other single treatments after 21 days. Additionally, almost no systemic undesired toxicity was detected during the observation period. We believe that the concept of LCIR as presented here offers a potential platform to overcome the resistance to conventional therapies by the incorporation with the energy metabolism inhibition approach.

Pharmacokinetics of panduratin A following oral administration of a Boesenbergia pandurata extract to rats.

Boesenbergia pandurata and its major active ingredient, panduratin A (PAN), exhibit antibacterial, anti-oxidant, anti-inflammatory, and anti-obesity effects. We explored the time course of the plasma and tissue (in the major organs, gums and skin) concentrations of PAN after oral administration of a B. pandurata extract to rats. Model-dependent analysis was used to quantify the skin distribution of PAN after systemic exposure. The PAN level peaked at 1.12 ± 0.22 µg/mL after 3 h, and then biexponentially decayed with a terminal half-life of 9 h. The mean clearance (Cl/F) was 2.33 ± 0.68 L/h/kg. The PAN levels in organs were in the following order (highest first): skin, lung, heart, gum, liver, spleen, kidney, and brain. For the first time, the time course of PAN levels in plasma and organs was investigated after oral administration of a BPE. This study helps to explain the pharmacological activities of PAN in the skin and gums. The pharmacokinetic model provided data in the plasma and skin concentrations of PAN, which are of fundamental importance to evaluate its efficacy.

Development of a gastroretentive delivery system for acyclovir by 3D printing technology and its in vivo pharmacokinetic evaluation in Beagle dogs.

Gastroretentive (GR) systems are designed to prolong gastric residence time to allow sustained absorption and improve the oral bioavailability of drugs with a narrow absorption window in the upper part of the gastrointestinal tract. The present study aimed to develop a GR system for acyclovir using 3D printing technology and evaluate its in vivo pharmacokinetics after oral administration in Beagle dogs. The system consisted of a gastro-floating device, which can float in the gastric fluid, prepared by a fused deposition modeling 3D printer and conventional acyclovir sustained-release (SR) tablet. The acyclovir SR tablet was inserted to the floating device to allow sustained release of the drug in the stomach. The buoyancy and sustained-release property of the developed GR system were determined using an in vitro dissolution test, in vivo pharmacokinetic study, and abdominal X-ray imaging in Beagle dogs. The in vivo dissolution profiles of the GR system were also predicted based on the in vivo pharmacokinetic data using a population pharmacokinetic (POP-PK) model. In the dissolution test, the sustained-release characteristic of the GR system was identified with a time corresponding to 80% dissolution (T80) of 2.52 h. Following oral administration of the GR system, the time to reach the maximum concentration (Tmax) of acyclovir was significantly prolonged, whereas the maximum concentration (Cmax) decreased and the area under the curve increased compared with those obtained after the administration of immediate-release and SR tablets, indicating prolonged absorption. By X-ray imaging, we showed that the developed GR system stayed in the stomach for more than 12 h. The POP-PK model successfully described the observed plasma concentration-time data and predicted the in vivo biphasic dissolution profiles of the GR system, which was significantly different from the in vitro dissolution. The developed GR system could be applied to various drugs and had great prospects in the design and development of novel controlled-release formulations.

Small gold nanorods-loaded hybrid albumin nanoparticles with high photothermal efficacy for tumor ablation.

Photothermal therapy using gold nanorods (AuNRs) has gained great attention for cancer therapy because AuNRs emit heat and induce tumor cell death responding to the near infrared light. However, the anticancer efficiency of AuNRs alone is undermined by its poor in vivo stability and potential toxicity. The prime purpose of this study was to send more AuNRs into tumors to more fully ablate them. For this, we fabricated hybrid albumin nanoparticles encapsulating small AuNRs (AuNRs-Alb-NPs), which take advantage of biocompatible albumin as a carrier, with better tumor targetability and high in vivo photothermal activity. The sizes of length/width of AuNRs were approximately 20.5 nm and 4.6 nm, respectively, showing a 4.5 aspect ratio, and the size of the resulting AuNRs-Alb-NPs was ˜130 nm, all of which are favorable for glomerular filtration and passive tumor targeting via extravasation. We chose the best formulation for AuNRs-Alb-NPs by in vitro cytotoxicity based on photothermal conversion efficiency considering the incorporated number of AuNRs. Visualized by a photothermal camera, the local tumor temperature of mice treated with AuNRs-Alb-NPs increased to 57℃, which was sufficient for the hyperthermal effect with 808 nm laser irradiation. Subsequently, AuNRs-Alb-NPs displayed remarkably better tumor ablation vs. naïve formulation of AuNRs (tumor volume: 73.8 ± 105.8 vs. 1455.3 ± 310.4 mm3 at day 8) in the glioblastoma N2a tumor-bearing mice. Most of all, we demonstrated, using photoacoustic imaging and inductively coupled plasma mass spectrometry, that this much better tumor ablation was due to enhanced tumor targeting with albumin nanoparticles. We believe our AuNRs-Alb-NPs should be considered promising photothermal agents that are safer, have good targetability, and exhibit excellent tumor ablation.

Quantitative Prediction of Oral Bioavailability of a Lipophilic Antineoplastic Drug Bexarotene Administered in Lipidic Formulation Using a Combined In Vitro Lipolysis/Microsomal Metabolism Approach.

For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.

Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice.

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, Kp, for the liver and kidney were higher in the piperine-pretreated group, while the Kp for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

Alterations of Gefitinib Pharmacokinetics by Co-administration of Herbal Medications in Rats.

OBJECTIVE: To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib (Iressa®) and the oriental medications Guipi Decoction (, GPD, Guibi-tang in Korean) and Bawu Decoction (, BWD, Palmul-tang in Korean). METHODS: Methylcellulose (MC, control), GPD (1,200 mg/kg), or BWD (6,000 mg/kg) was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib (10 mg/kg) was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefitinib (10 mg/kg) was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis. RESULTS: Gefitinib was rapidly absorbed and showed a monoexponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration (Cmax, P<0.05) and area under the curve (P<0.05), and a delayed time to reach Cmax (Tmax, P<0.01) were observed in both single- and multipledose BWD-pretreated rats compared with the control rats. CONCLUSIONS: BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.

Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling.

S-1 (TS-1®) is an oral fluoropyrimidine anticancer agent containing tegafur, oteracil, and gimeracil. Sipjeondaebo-tang (SDT) is a traditional oriental herbal medicine that has potential to alleviate chemotherapy-related adverse effects. The aim of the present study was to evaluate the effect of SDT on the pharmacokinetics of S-1. Sprague-Dawley rats were pretreated with a single dose or repeated doses of SDT for seven consecutive days (1200 mg/kg/day). After the completion of pretreatment with SDT, S-1 was orally administered and plasma concentrations of tegafur, its active metabolite 5-FU, and gimeracil were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). A population pharmacokinetic model was developed to evaluate the effect of SDT on pharmacokinetics of tegafur and 5-FU. Although a single dose of SDT did not have any significant effect, the absorption rate of tegafur decreased, and the plasma levels of 5-FU reduced significantly in rats pretreated with SDT for seven days in parallel to the decreased gimeracil concentrations. Population pharmacokinetic modeling also showed the enhanced elimination of 5-FU in the SDT-pretreated group. Repeated doses of SDT may inhibit the absorption of gimeracil, an inhibitor of 5-FU metabolism, resulting in enhanced elimination of 5-FU and decrease its plasma level.

Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine.

Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413.

Targeted co-delivery of polypyrrole and rapamycin by trastuzumab-conjugated liposomes for combined chemo-photothermal therapy.

Trastuzumab is a therapeutic monoclonal antibody that selectively recognizes HER2/neu receptor for targeting breast cancers. In this study, we aimed to present a strategy to combine chemo and phototherapy and targeted delivery via monoclonal antibody for enhanced anticancer effects. We co-loaded a chemotherapeutic agent, rapamycin, and a photosensitizer, polypyrrole, in trastuzumab-conjugated liposomes (LRPmAb) for combined chemo-photothermal therapy. LRPmAb had small size (172.2±9.6nm), narrow distribution, and negative ζ-potential (-12.0±0.3mV). In addition, LRPmAb showed pH- and temperature-dependent release profiles. LRPmAb showed significantly enhanced uptake in BT-474 cells, a natural HER2/neu expressing cell line. We found that these LRPmAb were effective in delivering rapamycin and showed higher therapeutic efficacy in breast cancer cells overexpressing HER2/neu receptors compared with cells that did not overexpress these receptors. Furthermore, LRPmAb showed synergistic activity against rapamycin-sensitive and resistant cell lines in vitro. These findings indicated that LRPmAb-mediated drug delivery could improve the therapeutic efficacy against breast cancer and overcome drug resistance.

Modulation of Pharmacokinetic and Cytotoxicity Profile of Imatinib Base by Employing Optimized Nanostructured Lipid Carriers.

PURPOSE: To prepare, optimize and characterize imatinib-loaded nanostructured lipid carriers (IMT-NLC), and evaluate their pharmacokinetic and cytotoxicity characteristics. METHODS: IMT-NLC was prepared by hot homogenization method, and optimized by an approach involving Plackett-Burman design (PBD) and central composite design (CCD). An in vivo pharmacokinetic study was conducted in rats after both oral and intravenous administration. The in vitro cytotoxicity was evaluated by MTT assay on NCI-H727 cell-lines. RESULTS: PBD screening, followed by optimization by CCD and desirability function, yielded an optimized condition of 0.054, 6% w/w, 2.5% w/w and 1.25% w/v for organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), amount of lecithin (Lec) and amount of Tween® 20 (Tw20) respectively. The optimized IMT-NLC exhibited a particle size (Sz) of 148.80 ± 1.37 nm, polydispersity index (PDI) 0.191 ± 0.017 of and ζ-potential of -23.0 ± 1.5 mV, with a drug loading (DL) of 5.48 ± 0.01% and encapsulation efficiency (EE) of 97.93 ± 0.03%. IMT-NLC displayed sustained IMT release in vitro, significantly enhanced in vivo bioavailability of IMT after intravenous and oral administration, and greater in vitro cytotoxicity on NCI-H727 cells, compared with free IMT. CONCLUSION: A combined DoE approach enabled accurate optimization and successful preparation of IMT-NLC with enhanced in vivo pharmacokinetic and in vitro cytotoxicity characteristics.

Quality evaluation and pattern recognition analyses of bioactive marker compounds from Farfarae Flos using HPLC/PDA.

The flower bud of Tussilago farfara L., called Farfarae Flos, has traditionally been used in Oriental medicine for the treatment of bronchitis and asthma. To establish a standard for quality control as well as the reliable identification of Farfarae Flos, the contents of five standards, rutin (1), isoquercetin (2), 3,5-dicaffeoylquinic acid (3), tussilagone (4), and tussilagonone (5), were determined by quantitative high-performance liquid chromatography (HPLC)/photodiode array (PDA) analysis. The five standards were separated on a YoungJinBioChrom Aegispak C18-L (250-mm×4.6-mm, 5-µm) column by gradient elution using 0.03% trifluoroacetic acid in water (A), with acetonitrile (B) as the mobile phase. The flow rate was 1.0 mL/min, and the UV detector wavelength was set at 220 nm. The method was successfully used in the analysis of Farfarae Flos from different geographic origins with relatively simple conditions and procedures, and the results demonstrated satisfactory linearity, recovery, precision, accuracy, stability, and robustness. The HPLC analytical method for pattern recognition analysis was validated by repeated analysis of 62 Farfarae Flos samples. This result indicated that the established HPLC/PDA method is suitable for quantitation and pattern recognition analyses for the quality evaluation of Farfarae Flos.

Preparation and evaluation of 17-allyamino-17-demethoxygeldanamycin (17-AAG)-loaded poly(lactic acid-co-glycolic acid) nanoparticles.

In the present study, we developed the novel 17-allyamino-17-demethoxygeldanamycin (17-AAG)-loaded poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles (NPs) using the combination of sodium lauryl sulfate and poloxamer 407 as the anionic and non-ionic surfactant for stabilization. The PLGA NPs were prepared by emulsification/solvent evaporation method. Both the drug/polymer ratio and phase ratio were 1:10 (w/w). The optimized formulation of 17-AAG-loaded PLGA NPs had a particle size and polydispersity index of 151.6 ± 2.0 and 0.152 ± 0.010 nm, respectively, which was further supported by TEM image. The encapsulation efficiency and drug loading capacity were 69.9 and 7.0%, respectively. In vitro release study showed sustained release. When in vitro release data were fitted to Korsmeyer-Peppas model, the n value was 0.468, which suggested that the drug was released by anomalous or non-Fickian diffusion. In addition, 17-AAG-loaded PLGA NPs in 72 h, displayed approximately 60% cell viability reduction at 10 µg/ml 17-AAG concentration, in MCF-7 cell lines, indicating sustained release from NPs. Therefore, our results demonstrated that incorporation of 17-AAG into PLGA NPs could provide a novel effective nanocarrier for the treatment of cancer.

Pharmacokinetic alteration of baclofen by multiple oral administration of herbal medicines in rats.

The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42-4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (C max) and longer time to reach C max (T max) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (F urine). The absorption rate (K a ) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.

Rapid screening of blood-brain barrier penetration of drugs using the immobilized artificial membrane phosphatidylcholine column chromatography.

The chromatographic capacity factors (kIAM) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (IAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The kIAM was determined using the mobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (kIAM/MWn). The correlation between kIAM/MWn and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro prediction method was validated with 7 newly synthesized PDE-4 inhibitors. The relationship between in vivo plasma-to-brain concentration ratios and in vitro CNS penetration was excellent (r = 0.959). The developed in vitro prediction method may be used as a rapid screening tool for BBB penetration of drugs with passive transport mechanism, with high success, low cost, and reproducibility.

Altered oral absorption of alcohol by combined aqueous extracts of four herbal plants in rats.

This study examined the effect of combined aqueous extracts (BHR) of Ginko biloba, Mentha arvensis var. piperascens, Citrus unshiu, and Pueraria lobata var. chinensis on oral absorption of alcohol in rats. The rats were pretreated with BHR, placebo solution identical to BHR without the herbal extract, and isotonic saline. Alcohol was administered orally at 1- and 3-g/kg doses and the absorption profiles were compared. After oral administration of 1-g/kg doses, mean area under the curve (AUC) and C(max) values were significantly reduced in BHR-treated rats (16.1 +/- 10.0 and 0.3 +/- 0.1 mg/ml, respectively) as compared with saline-treated (37.9 +/- 14.4 and 0.7 +/- 0.7 mg/ml, respectively) and placebo solution-treated (63.0 +/- 46.4 and 0.7 +/- 0.4 mg/ml, respectively) rats. Similarly, after administration of 3-g/kg doses, mean AUC and C(max) values in BHR-treated rats (188.1 +/- 119.7 mg(.)min/ml and 1.0 +/- 0.4 mg/ml) were significantly reduced over those in saline-treated rats (571.4 +/- 512.4 mg(.)min/ml and 1.8 +/- 0.9 mg/ml, respectively). The relative oral bioavailability of alcohol calculated as the ratio of AUC(BHR)/AUC(Saline) was 42.5% and 32.9% at 1- and 3-g/kg doses, respectively. The reduced serum alcohol levels as well as the reduced AUC and C(max) after pretreatment with BHR appear to be a result of a reduced systemic absorption not due to an increased metabolic clearance.

Effects of aloe, aloesin, or propolis on the pharmacokinetics of benzo[a]pyrene and 3-OH-benzo[a]pyrene in rats.

This study was conducted to examine the effects of aloe and aloesin on the weight gain and blood chemistry as well as the pharmacokinetics of benzo[a]pyrene (BaP) and 3-OH-BaP in rats. The rats treated with multiple doses of aloe and aloesin (100 mg/kg every 12 h for 14-19 d) did not show any significant changes in the weight gain and blood biochemical parameters. In addition, the effects of oral treatment with aloe, aloesin, and propolis on the absorption and pharmacokinetics of benzo[a]pyrene (BaP) and its metabolite, 3-OH-BaP, were studied in rats. The treatment with a single oral dose (200 mg/kg) of aloe, aloesin, and propolis did not alter the concentration-time profiles of BaP and 3-OH-BaP after iv and oral administration of BaP. At higher oral doses (500 mg/kg), the biliary excretion of BaP and the urinary excretion of 3-OH-BaP were significantly increased, but the urinary excretion of BaP and the fecal excretion of 3-OH-BaP remained unaltered. Whether high doses of aloe increase the overall elimination of BaP deserves further investigation.

Oral absorption and pharmacokinetics of rebamipide and rebamipide lysinate in rats.

Rebamipide is an anti-ulcer agent exhibiting a low aqueous solubility and a poor oral bioavailability. This study was conducted to examine if the rebamipide lysinate salt form would exhibit improved solubility profiles and higher oral bioavailability compared with rebamipide free acid. Both compounds showed pH-dependent solubility profiles, with the solubility of rebamipide lysinate dramatically improved at a median pH of 5.1 (17-fold increases) over free acid, but the improvement in the solubility was not as pronounced in artificial gastric and intestinal fluids (1.4- and 1.9-fold increases, respectively). The Cl, V(ss) and t1/2 in rats after i.v. injection of rebamipide (0.5 mg/kg) averaged 21.0 +/- 3.2 ml/min/kg, 0.3 +/- 0.0 L/kg, and 0.4 +/- 0.1 hr, respectively. No significant difference was observed in these parameters between rebamipide and rebamipide lysinate. Despite improved solubility profiles, the absolute oral bioavailability of rebamipide lysinate was not increased (5.1 vs. 4.8%) nor did AUC (407.8 vs. 383.6 ng x hr/ml) and C(max) (87.4 vs. 77.0 ng/ml) compared with rebamipide free acid. Rebamipide lysinate, however, showed a more rapid absorption, and initial serum drug concentrations were higher than those found for rebamipide free acid.