Endogenous Plasma Kynurenic Acid in Human: A Newly Discovered Biomarker for Drug-Drug Interactions Involving Organic Anion Transporter 1 and 3 Inhibition.

As an expansion investigation of drug-drug interaction (DDI) from previous clinical trials, additional plasma endogenous metabolites were quantitated in the same subjects to further identify the potential biomarkers of organic anion transporter (OAT) 1/3 inhibition. In the single dose, open label, three-phase with fixed order of treatments study, 14 healthy human volunteers orally received 1000 mg probenecid alone, or 40 mg furosemide alone, or 40 mg furosemide at 1 hour after receiving 1000 mg probenecid on days 1, 8, and 15, respectively. Endogenous metabolites including kynurenic acid, xanthurenic acid, indo-3-acetic acid, pantothenic acid, p-cresol sulfate, and bile acids in the plasma were measured by liquid chromatography-tandem mass spectrometry. The Cmax of kynurenic acids was significantly increased about 3.3- and 3.7-fold over the baseline values at predose followed by the treatment of probenecid alone or in combination with furosemide respectively. In comparison with the furosemide-alone group, the Cmax and area under the plasma concentration-time curve (AUC) up to 12 hours of kynurenic acid were significantly increased about 2.4- and 2.5-fold by probenecid alone, and 2.7- and 2.9-fold by probenecid plus furosemide, respectively. The increases in Cmax and AUC of plasma kynurenic acid by probenecid are comparable to the increases of furosemide Cmax and AUC reported previously. Additionally, the plasma concentrations of xanthurenic acid, indo-3-acetic acid, pantothenic acid, and p-cresol sulfate, but not bile acids, were also significantly elevated by probenecid treatments. The magnitude of effect size analysis for known potential endogenous biomarkers demonstrated that kynurenic acid in the plasma offers promise as a superior addition for early DDI assessment involving OAT1/3 inhibition. SIGNIFICANCE STATEMENT: This article reports that probenecid, an organic anion transporter (OAT) 1 and OAT3 inhibitor, significantly increased the plasma concentrations of kynurenic acid and several uremic acids in human subjects. Of those, the increases of plasma kynurenic acid exposure are comparable to the increases of furosemide by OAT1/3 inhibition. Effect size analysis for known potential endogenous biomarkers revealed that plasma kynurenic acid is a superior addition for early drug-drug interaction assessment involving OAT1/3 inhibition.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. AIM OF THE STUDY: The present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. MATERIALS AND METHODS: Wistar rats (175-200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. RESULTS: The VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. CONCLUSION: The results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.

Cuminaldehyde potentiates the antimicrobial actions of ciprofloxacin against Staphylococcus aureus and Escherichia coli.

Escherichia coli and Staphylococcus aureus are important agents of urinary tract infections that can often evolve to severe infections. The rise of antibiotic-resistant strains has driven the search for novel therapies to replace the use or act as adjuvants of antibiotics. In this context, plant-derived compounds have been widely investigated. Cuminaldehyde is suggested as the major antimicrobial compound of the cumin seed essential oil. However, this effect is not fully understood. Herein, we investigated the in silico and in vitro activities of cuminaldehyde, as well as its ability to potentiate ciprofloxacin effects against S. aureus and E. coli. In silico analyses were performed by using different computational tools. The PASS online and SwissADME programmes were used for the prediction of biological activities and oral bioavailability of cuminaldehyde. For analysis of the possible toxic effects and the theoretical pharmacokinetic parameters of the compound, the Osiris, SwissADME and PROTOX programmes were used. Estimations of cuminaldehyde gastrointestinal absorption, blood brain barrier permeability and skin permeation by using SwissADME; and drug likeness and score by using Osiris, were also evaluated The in vitro antimicrobial effects of cuminaldehyde were determined by using microdilution, biofilm formation and time-kill assays. In silico analysis indicated that cuminaldehyde may act as an antimicrobial and as a membrane permeability enhancer. It was suggested to be highly absorbable by the gastrointestinal tract and likely to cross the blood brain barrier. Also, irritative and harmful effects were predicted for cuminaldehyde if swallowed at its LD50. Good oral bioavailability and drug score were also found for this compound. Cuminaldehyde presented antimicrobial and anti-biofilm effects against S. aureus and E. coli.. When co-incubated with ciprofloxacin, it enhanced the antibiotic antimicrobial and anti-biofilm actions. We suggest that cuminaldehyde may be useful as an adjuvant therapy to ciprofloxacin in S. aureus and E. coli-induced infections.

Mangiferin glycethosomes as a new potential adjuvant for the treatment of psoriasis.

Mangiferin, a natural compound isolated from Mangifera indica L, was incorporated in glycerosomes, ethosomes and alternatively in glycerol-ethanol phospholipid vesicles (glycethosomes). Actually, only glycethosomes were able to stably incorporate the mangiferin that was loaded at increasing concentrations (2, 4, 6, 8 mg/mL). The morphology, size distribution, rheological properties, surface charge and entrapment efficiency of prepared vesicles were deeply measured. All vesicles were mainly spherical, oligolamellar, small in size (~145 nm) and negatively charged (~-40 mV), as confirmed by cryo-TEM observation and dynamic laser light scattering measurements. The higher concentration of mangiferin (8 mg/mL) allowed an increase of vesicle mean diameter up to ~288 nm. The entrapment efficiency was inversely proportional to the amount of loaded mangiferin. In vitro studies performed by using human abdominal skin, underlined that, the dose-dependent ability of vesicles to promote mangiferin retention in epidermis. In addition, glycethosomes were highly biocompatible and showed a strong ability to protect in vitro the fibroblasts against damages induced by hydrogen peroxide. In vivo results underlined the superior ability of mangiferin loaded glycethosomes respect to the mangiferin dispersion to promote the heal of the wound induced by TPA, confirming their potential application for the treatment of psoriasis or other skin disorders.

Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children.

BACKGROUND: There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. METHODS: IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. RESULTS: There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 µg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. CONCLUSIONS: Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01322009.

Differential distribution of probenecid as detected by on-tissue mass spectrometry.

We demonstrate, by means of on-tissue mass spectrometry of tissue sections, that the drug probenecid can penetrate the blood-brain barrier. This method holds general promise for the detection and distribution of small molecule drugs within organ and tissue compartments.

Effects of curcumin on bleomycin-induced apoptosis in human malignant testicular germ cells

Testicular cancer is the most common cancer among young men of reproductive age. Bleomycin is a frequently used drug for the treatment of several malignancies and is part of the chemotherapy protocols in testicular cancer. Bleomycin causes an increase in oxidative stress which has been shown to induce apoptosis in cancer cells. Curcumin (diferuloylmethane), an active component of the spice turmeric, has attracted interest because of its anti-inflammatory and chemopreventive activities. However, no study has been carried out so far to elucidate its interaction with bleomycin in testicular cancer cells. In this study, we investigated the effects of curcumin and bleomycin on apoptosis signalling pathways and compared the effects of bleomycin with H2O2 which directly produces reactive oxygen species. We measured apoptosis markers such as caspase-3, caspase-8, and caspase-9 activities and Bcl-2, Bax, and Cyt-c levels in NCCIT cells incubated with curcumin (5 ìM), bleomycin (120 ìg/ml), bleomycin + curcumin, H2O2 (35 ìM), and H2O2 + curcumin for 72 h. Curcumin, bleomycin, and H2O2 caused apoptosis indicated as increases in caspase-3, caspase-8, and caspase-9 activities and Bax and cytoplasmic Cyt-c levels and a decrease in Bcl-2 level. Concurrent use of curcumin with bleomycin decreased caspase activities and Bax and Cyt-c levels compared to their separate effects in NCCIT cells. Our findings suggest that concurrent use of curcumin during chemotherapy in testis cancer should be avoided due to the inhibitory effect of curcumin on bleomycin-induced apoptosis (AU)

Pharmacokinetics of low-dose cidofovir in kidney transplant recipients with BK virus infection.

BACKGROUND: BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen are not known in kidney transplant recipients. METHODS: We investigated the pharmacokinetics (PK) of low-dose cidofovir (0.24 - 0.62 mg/kg) both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design. RESULTS: The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m(2) (range: 17-75 mL/min/1.73 m(2) ). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir PK. Maximum cidofovir plasma concentrations, which averaged approximately 1 µg/mL, were significantly below the 36 µg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P > 0.05). CONCLUSIONS: Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r(2) = 0.8 without probenecid; r(2) = 0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships to optimize the cidofovir dosing regimen for BKV infection.

Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules.

Chitosan (CS), a cationic polysaccharide, is widely regarded as a safe and efficient intestinal absorption enhancer of therapeutic macromolecules, owing to its inherent mucoadhesive feature and ability to modulate the integrity of epithelial tight junctions reversibly. By using CS-based nanoparticles, many studies have attempted to protect the loaded macromolecules against acidic denaturation and enzymatic degradation, prolong their intestinal residence time, and increase their absorption by the intestinal epithelium. Derivatives of CS such as quaternized CS, thiolated CS and carboxylated CS have also been examined to further enhance its effectiveness in oral absorption of macromolecular drugs. This review article describes the synthesis of these CS derivatives and their characteristics, as well as their potential transport mechanisms of macromolecular therapeutics across the intestinal biological membrane. Recent advances in using CS and its derivatives as carriers for oral delivery of hydrophilic macromolecules and their effects on drug transport are also reviewed.

Oral drug delivery systems using chemical conjugates or physical complexes.

Oral delivery of therapeutics is extremely challenging. The digestive system is designed in a way that naturally allows the degradation of proteins or peptides into small molecules prior to absorption. For systemic absorption, the intact drug molecules must traverse the impending harsh gastrointestinal environment. Technologies, such as enteric coating, with oral dosage formulation strategies have successfully provided the protection of non-peptide based therapeutics against the harsh, acidic condition of the stomach. However, these technologies showed limited success on the protection of therapeutic proteins and peptides. Importantly, inherent permeability coefficient of the therapeutics is still a major problem that has remained unresolved for decades. Addressing this issue in the context, we summarize the strategies that are developed in enhancing the intestinal permeability of a drug molecule either by modifying the intestinal epithelium or by modifying the drug itself. These modifications have been pursued by using a group of molecules that can be conjugated to the drug molecule to alter the cell permeability of the drug or mixed with the drug molecule to alter the epithelial barrier function, in order to achieve the effective drug permeation. This article will address the current trends and future perspectives of the oral delivery strategies.

Pharmaceutical nanotechnology for oral delivery of anticancer drugs.

Oral chemotherapy is an important topic in the 21st century medicine, which may radically change the current regimen of chemotherapy and greatly improve the quality of life of the patients. Unfortunately, most anticancer drugs, especially those of high therapeutic efficacy such as paclitaxel and docetaxel, are not orally bioavailable due to the gastrointestinal (GI) drug barrier. The molecular basis of the GI barrier has been found mainly due to the multidrug efflux proteins, i.e. P-type glycoproteins (P-gp), which are rich in the epithelial cell membranes in the GI tract. Medical solution for oral chemotherapy is to apply P-gp inhibitors such as cyclosporine A, which, however, suppress the body's immune system either, thus causing medical complication. Pharmaceutical nanotechnology, which is to apply and further develop nanotechnology to solve the problems in drug delivery, may provide a better solution and thus change the way we make drug and the way we take drug. This review is focused on the problems encountered in oral chemotherapy and the pharmaceutical nanotechnology solutions such as prodrugs, nanoemulsions, dendrimers, micelles, liposomes, solid lipid nanoparticles and nanoparticles of biodegradable polymers. Proof-of-concept in vitro and in vivo results for oral delivery of anticancer drugs by the various nanocarriers, which can be found so far from the literature, are provided.

Bacterial efflux pumps involved in multidrug resistance and their inhibitors: rejuvinating the antimicrobial chemotherapy.

Active efflux of antibiotics is one of the major mechanisms of drug resistance in bacteria. The efflux process is mediated by membrane transporters with a large variety of unrelated compounds as their substrates. Though these pumps are responsible for the low intrinsic resistance of a bacterium to a drug, their overexpression, accumulation of mutations in these proteins and their synergy with other drug resistance mechanisms hampers effective antimicrobial treatment. As efflux pumps have been reported to play vital roles in mediating multidrug resistance in clinical isolates from varied geographic locations and varied populations, the inhibition of efflux pumps appears to be an attractive approach to combat the problem of drug resistance. Efflux pump inhibitors can be utilized for increasing the antibiotic concentration inside a pathogenic cell making these drugs more effective, reduce the accumulation of other resistance mechanisms in a cell and for diagnostic purposes to evaluate the presence and contribution of the efflux mechanism in a pathogen. A large number of inhibitors have been discovered and patented in last two decades but the process of discovery, testing and commercialization is rather slow. Some of the important inhibitors include the energy decouplers, phenothiazines, analogs of popular antibiotics, inhibitors of serotonin re-uptake, to name a few, that have been used as adjuvants in the antimicrobial chemotherapy to potentiate the activity of some important antimicrobials in deadly pathogens that have worried the mankind since long. This review describes the role of efflux pumps in governing the resistance phenotype of a pathogen, efflux pumps found in bacteria and the efflux pump inhibitors that have been studied and patented so far.

Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery.

This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer-drug conjugates, as a function of physicochemical properties will further need to be assessed.

Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001).

For use in chronic oral chemotherapeutic regimens, the potent anticancer drug docetaxel needs a solid oral dosage form. Because docetaxel has a very low permeability and a very low aqueous solubility (biopharmaceutical classification system class IV), a pharmacokinetic booster was combined with a newly developed solid dispersion formulation to improve the oral bioavailability of docetaxel. The best performing solid dispersion was a 1/9/1 w/w/w ternary mixture of docetaxel, polyvinylpyrrolidone (PVP)-K30 and sodium lauryl sulphate (SLS). In a phase I clinical trial, with ritonavir as pharmacokinetic booster, the docetaxel premix solution (TAXOTERE) was pharmacokinetically evaluated against the solid dispersion formulation filled into hard gelatin capsules (ModraDoc001 15 mg capsules). There were no significant differences between the pharmacokinetic parameters of docetaxel after administration of docetaxel premix solution or ModraDoc001 15 mg capsules, although there was a trend towards a higher and more variable exposure to docetaxel after oral administration of docetaxel premix solution (513 ± 219 vs. 790 ± 669 ngh/mL). The low inter-individual variability of docetaxel exposure (44%), the dosing accuracy, and the absence of ethanol and polysorbate are major advantages of ModraDoc001 15 mg capsules over docetaxel premix solution.

Pharmacokinetic evaluation of zoledronic acid.

INTRODUCTION: Increased bone resorption is associated with several diseases, including osteoporosis, bone metastases and Paget's disease of bone. Zoledronic acid (ZA) is the most potent of the clinically available bisphosphonates. In addition to its antiresorptive activity, there has been increasing evidence to suggest that it also has anticancer properties. AREAS COVERED: This article is complied through PubMed and Medline databases searches on ZA. In this review, the authors summarize the current knowledge (up to December 2010) on the pharmacodynamic and pharmacokinetic properties of ZA. EXPERT OPINION: ZA is a well-tolerated and effective drug in the management of metabolic as well as cancer-related bone disease. Clinical benefits in cancer patients include improvement in bone pain, reduction in skeletal events and delay of time to first skeletal event. However, novel indications for this drug are emerging from clinical studies in early breast cancer. Recent findings suggest that the addition of ZA to endocrine therapy can significantly prevent bone loss in premenopausal patients. Increasing evidence also indicates a potential anticancer activity of ZA, although this property needs to be further explored.

Gelucire44/14 as a novel absorption enhancer for drugs with different hydrophilicities: in vitro and in vivo improvement on transcorneal permeation.

The objective of this study was to investigate the application of Gelucire44/14 as a novel absorption enhancer in ophthalmic drug delivery system. Six compounds, namely ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin in the order of increasing lipophilicity were selected as model drugs. The effect of Gelucire44/14 on transcorneal permeation was evaluated across excised rabbit cornea. Ocular irritation and precorneal retention time were assessed. Additionally, aqueous humor pharmacokinetic test was performed by microdialysis. The results indicated that Gelucire44/14, at a concentration of 0.05% or 0.1% (w/v), was found to maximally increase the apparent permeability coefficient by 6.47-, 4.14-, 3.50-, 3.97-, 2.92-, and 1.86-fold for ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin, respectively (p < 0.05). Moreover, Gelucire44/14 was nonirritant at broad concentrations of 0.025%-0.4% (w/v). Pharmacokinetic tests showed that Gelucire44/14 promoted ocular bioavailability of the compounds as indicated by 5.40-, 4.03-, 3.46-, 3.57-, 2.77-, and 1.77-fold maximal increase in the area under the curve for the drugs aforementioned, respectively (p < 0.01). Therefore, Gelucire44/14 exerted a significant improvement on the permeation of both hydrophilic and lipophilic compounds, especially hydrophilic ones. Hence, Gelucire44/14 can be considered as a safe and effective absorption enhancer for ophthalmic drug delivery system.

Complexation with phosphatidyl choline as a strategy for absorption enhancement of boswellic acid.

Boswellic acids (BAs) are isolated from oleo gum resin of Boswellia serrata and are reported to be effective as anti-inflammatory, hypolipidemic, immunomodulatory, and anti-tumor. Pharmacokinetic studies of boswellic acid reveal its poor absorption through the intestine. The objective of the present study is to enhance bioavailability of boswellic acid by its complexation with phosphatidylcholine. A complex of boswellic acid was prepared with phosphatidylcholine and characterized on the basis of solubility, melting point, TLC, and IR. An everted intestine sac technique was used to study ex-vivo drug absorption of boswellic acid-phosphatidylcholine (BA-PC) complex and plain boswellic acid. Anti-inflammatory activity of the complex was compared with boswellic acid in carrageenan-induced paw edema in rats. Hypolipidemic activity was also evaluated in Triton-induced hyperlipidemia. The complex was also converted into vesicles (phytosomes) and compared with other vesicular systems (liposomes and niosomes) by evaluating its anti-inflammatory effect. Analytical reports along with spectroscopic data revealed the formation of a complex. The results of ex-vivo study show that BA-PC complex has significantly increased absorption compared with boswellic acid, when given in equimolar doses. The complex showed better anti-inflammatory and hypolipidemic activity as compared to BA. Among all vesicular systems phytosomes showed maximum anti-inflammatory activity. Enhanced bioavailability of the BA-PC complex may be due to the amphiphilic nature of the complex, which greatly enhance the water and lipid solubility of the boswellic acid. The present study clearly indicates the superiority of complex over boswellic acid, in terms of better absorption, enhanced bioavailability and improved pharmacokinetics.

Pharmacokinetic properties and bioequivalence of two compound formulations of 1500 mg ampicillin (1167 mg)/probenecid (333 mg): a randomized-sequence, single-dose, open-label, two-period crossover study in healthy Chinese male volunteers.

BACKGROUND: Ampicillin/probenecid is an antimicrobial formulation indicated for the treatment of respiratory, urinary tract, and gastrointestinal infections. Ampicillin sodium is the active antimicrobial ingredient that can act on the phase of bacterial breeding and inhibit the biosynthesis of bacterial mucopeptide in the cell wall. Probenecid acts synergistically by competitively inhibiting an organic anion transporter in renal tubules, increasing the plasma concentrations, and thus extending the plasma elimination t(1/2). OBJECTIVE: The aim of this study was to assess and compare the pharmacokinetic (PK) properties, bioavailability, and bioequivalence of a newly developed dispersible tablet formulation (test) of ampicillin/ probenecid with those of an established branded capsule formulation (reference) in healthy Chinese male volunteers. METHODS: A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 6 dispersible tablets (test) or branded capsules (reference) (1500 mg total; 250 mg each containing ampicillin 194.5 mg and probenecid 55.5 mg), followed by a 7-day washout period and administration of the alternate formulation. Plasma samples were collected over a 24-hour period following administration and analyzed for ampicillin and probenecid content by HPLC. PK parameters such as C(max), AUC(0-t), and AUC(0-infinity) were also determined. The formulations were considered bioequivalent if the geometric mean ratios of the log-transformed C(max) and AUC values were within the equivalence range (80%-125%) predetermined by the State Food and Drug Administration (SFDA) of the People's Republic of China. Tolerability was based on the observation of adverse events (AEs), monitoring of vital signs (blood pressure, heart rate, temperature, electrocardiography) and laboratory tests (hematology, blood biochemistry, hepatic function, urinalysis), and subject's interview on AEs. RESULTS: The study was performed in 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.2] years; weight, 64.1 [5.5] kg; height, 173.7 [5.3] cm; and body mass index, 21.2 [1.6] kg/m(2)). The mean (SD) C(max), T(max), AUC(0-24), and AUC(0-infinity) after administration of the test and reference formulations, respectively, were as follows: ampicillin, C(max), 13.45 (3.43) versus 15.04 (5.68) microg/mL, T(max), 1.58 (0.49) versus 1.78 (0.55) hours, AUC(0-24), 50.78 (13.39) versus 57.44 (17.27) micro/mL/h, and AUC(0-infinity), 51.95 (13.45) versus 58.74 (17.19) microg/mL/h; probenecid, C(max), 15.56 (2.94) versus 16.01 (2.88) microg/mL, T(max), 2.85 (0.78) versus 3.30 (1.51) hours, AUC(0-24), 129.23 (27.59) versus 127.29 (26.89) microg/mL/h, and AUC(0-infinity) 133.85 (28.80) versus 131.21 (28.25) microg/mL/h. On ANOVA, neither period nor sequence effects were observed for any of the PK properties. The 90% CIs of ampicillin for the log-transformed ratios of C(max), AUC(0-24), and AUC(0-infinity)) were 86.5% to 108.0%, 96.7% to 107.8%, and 83.3% to 100.7%, respectively, and the corresponding values for probenecid were 90.2% to 108.3%, 96.8% to 107.8%, and 97.2% to 108.5%. No AEs were observed or reported up to 1 week after study end. CONCLUSIONS: In this small study in healthy Chinese male volunteers, a single 1500-mg dose of the dispersible tablet formulation (test) of ampicillin/probenecid met the SFDA's regulatory criteria for bioequivalence to the reference capsule formulation based on the rate and extent of absorption. Both formulations were well tolerated.

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid.

AIMS: Probenecid influences transport processes of drugs at several sites in the body and decreases elimination of several quinolones. We sought to explore extent, time course, and mechanism of the interaction between ciprofloxacin and probenecid at renal and nonrenal sites. METHODS: A randomized, two-way crossover study was conducted in 12 healthy volunteers (in part previously published Clin Pharmacol Ther 1995; 58: 532-41). Subjects received 200 mg ciprofloxacin as 30-min intravenous infusion without and with 3 g probenecid divided into five oral doses. Drug concentrations were analysed by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography. Ciprofloxacin and its 2-aminoethylamino-metabolite (M1) in plasma and urine with and without probenecid were modelled simultaneously with WinNonlin. RESULTS: Data are ratio of geometric means (90% confidence intervals). Addition of probenecid reduced the median renal clearance from 23.8 to 8.25 l h(-1)[65% reduction (59, 71), P < 0.01] for ciprofloxacin and from 20.5 to 8.26 l h(-1) (66% reduction (57, 73), P < 0.01] for M1 (estimated by modelling). Probenecid reduced ciprofloxacin nonrenal clearance by 8% (1, 14) (P < 0.08). Pharmacokinetic modelling indicated competitive inhibition of the renal tubular secretion of ciprofloxacin and M1 by probenecid. The affinity for the renal transporter was 4.4 times higher for ciprofloxacin and 3.6 times higher for M1 than for probenecid, based on the molar ratio. Probenecid did not affect volume of distribution of ciprofloxacin or M1, nonrenal clearance or intercompartmental clearance of ciprofloxacin. CONCLUSIONS: Probenecid inhibited the renal tubular secretion of ciprofloxacin and M1, probably by a competitive mechanism and due to reaching >100-fold higher plasma concentrations. Formation of M1, nonrenal clearance and distribution of ciprofloxacin were not affected.

Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect.

To examine possible blood-brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using [(3)H]pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of [(3)H]pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit [(3)H]pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentration-dependent manner by amitriptyline, fluvoxamine and mexiletine with K(i) values of 13, 65, and 44 microM, respectively. These K(i) values are 5-300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations.