Do Vitamin D Level and Dietary Calcium Intake Modify the Association Between Loop Diuretics and Bone Health?

Loop diuretics (LD) may affect bone health by inhibiting renal calcium reuptake. However, whether vitamin D status and dietary calcium intake modify the association between LD and bone outcome is unclear. Therefore, this study aimed to evaluate whether vitamin D level or calcium intake modify the association between LD and various indices of bone health including bone mineral density (BMD) and Trabecular Bone Score (TBS). From The Rotterdam Study, a prospective population-based cohort study, we used data from 6990 participants aged > 45 year with a DXA scan (2002-2008), 6908 participants with femoral neck (FN)-BMD, 6677 participants with lumbar spine (LS)-BMD and 6476 participants with LS-TBS measurements. Use of LD was available from pharmacy dispensing records. Vitamin D (25(OH)D) level was measured in serum, and dietary calcium intake was measured with a validated food frequency questionnaire. Almost eight percent of the participants used LD. The association between LD (past-users compared to never-users) and LS-TBS was significantly different by 25(OH)D concentrations (P for interaction = 0.04). A significantly lower LS-TBS among LD past-users was observed for 25(OH)D ≥ 50 nmol/l compared to ≤ 20 and 20-50 nmol/l (ß = - 0.036, 95% CI - 0.060; - 0.013 vs. ß = - 0.012, 95% CI - 0.036; 0.013 and ß = - 0.031, 95% CI - 0.096; 0.034, respectively). However, no other significant effect modification by 25(OH)D and dietary calcium intake was found in the associations between LD use and bone health outcomes (P-interaction > 0.13). This study suggests that the association between LD use and indices of bone health is not consistently modified by vitamin D or dietary calcium intake.

Assessment of patient knowledge on warfarin: An item response theory approach.

WHAT IS KNOWN AND OBJECTIVE: There are no instruments to assess the patient's knowledge of oral anticoagulation with warfarin, in which the performance of the items has been evaluated through the item response theory. To evaluate psychometric properties of the Brazilian version of the Oral Anticoagulation Knowledge Test, using the item response theory. METHODS: This methodological study was developed in an anticoagulation clinic of a university hospital with a sample of 201 patients treated with warfarin. The item response theory was used to evaluate questions regarding psychometric properties and the performance of the Brazilian version of the Oral Anticoagulation Knowledge Test items. The unidimensionality hypothesis was analysed by decomposing the polychoric correlation and the Cronbach's alpha coefficient. An item characteristic curve of the 20 items of the instrument was made to identify the discrimination power of each item of the performance scale. RESULTS AND DISCUSSION: Correlations were positive and statistically significant among the 20 items, with a Cronbach's alpha coefficient of 0.82. The difficulty parameter ranged from -4.14 to 0.42. The discrimination parameter ranged from 0.41 to 1.89. The items regarding drug-drug/drug-food interactions were able to differentiate knowledge about oral anticoagulation with greater accuracy. WHAT IS NEW AND CONCLUSION: This study is the first that uses this methodology to evaluate the knowledge on oral anticoagulation therapy with warfarin. The evaluation using item response theory showed that the Brazilian version of the Oral Anticoagulation Knowledge Test is suitable for assessing the patient's knowledge of oral anticoagulation with warfarin. Thus, our findings confirmed the utility of this instrument and provided an essential point of reference for the structuring of health education activities that ensure the individualization of educational interventions in patients on warfarin.

Nutraceutical Boom in Cancer: Inside the Labyrinth of Reactive Oxygen Species.

In recent years, epidemiological studies have shown that food is a very powerful means for maintaining a state of well-being and for health prevention. Many degenerative, autoimmune and neoplastic diseases are related to nutrition and the nutrient-organism interaction could define the balance between health and disease. Nutrients and dietary components influence epigenetic phenomena and modify drugs response; therefore, these food-host interactions can influence the individual predisposition to disease and its potential therapeutic response. Do nutraceuticals have positive or negative effects during chemotherapy? The use of nutraceutical supplements in cancer patients is a controversial debate without a definitive conclusion to date. During cancer treatment, patients take nutraceuticals to alleviate drug toxicity and improve long-term results. Some nutraceuticals may potentiate the effect of cytotoxic chemotherapy by inducing cell growth arrest, cell differentiation, and alteration of the redox state of cells, but in some cases, high levels of them may interfere with the effectiveness of chemotherapy, making cancer cells less reactive to chemotherapy. In this review, we highlighted the emerging opinions and data on the pros and cons on the use of nutraceutical supplements during chemotherapy.

Effect of Osmolality on the Pharmacokinetic Interaction between Apple Juice and Atenolol in Rats.

A recent clinical study reported that the ingestion of apple juice (AJ) markedly reduced the plasma concentration of atenolol; however, our in vitro study showed that atenolol may not be a substrate of organic anion transporting polypeptide 2B1 (OATP2B1), so this AJ-atenolol interaction cannot be explained by inhibition of OATP2B1. On the other hand, we more recently showed that the solution osmolality influences gastrointestinal (GI) water volume, and this may indirectly affect intestinal drug absorption. In this study, we examined whether the osmolality dependence of water dynamics can account for AJ-atenolol interactions by evaluating the GI water volume and the atenolol aborption in the presence of AJ in rats. Water absorption was highest in purified water, followed by saline and isosmotic mannitol solution, and the lowest in AJ, confirming that water absorption is indeed osmolality-dependent. Interestingly, AJ showed apparent water secretion into the intestinal lumen. The intestinal concentration of FD-4, a nonpermeable compound, after administration in AJ was lower than the initial concentration, whereas that in purified water was greater than the initial concentration. Further, the fraction of atenolol absorbed in intestine was significantly lower in AJ or hyperosmotic mannitol solution (adjusted to the osmolality of AJ) than after administration in purified water. Comparable results were observed in an in vivo pharmacokinetic study in rats. Our results indicate that orally administered AJ has a capacity to modulate luminal water volume depending on the osmolality, and this effect may result in significant AJ-atenolol interactions.

Pharmacokinetic interaction between modified Atkins diet and antiepileptic drugs in adults with drug-resistant epilepsy.

OBJECTIVE: The aim was to examine the influence of modified Atkins diet on serum concentration of antiepileptic drugs (AEDs). METHODS: Prospective data from 63 adult patients with either focal or generalized drug-resistant epilepsy recruited to 12-week dietary treatment as add-on to AEDs are analyzed. AED serum concentrations, ketones, glucose, and hemoglobin A1c were measured before and after the dietary intervention. Paired t test was used and Spearman correlation coefficient, r, was estimated. RESULTS: Mean age was 37 years (range 16-65 years). Mean serum concentrations of carbamazepine, clobazam, and valproate were significantly reduced after 4 and 12 weeks of the diet period (<.001 ≤ P ≤ .02). Levels of lacosamide, lamotrigine, and topiramate were less reduced (.02 ≤ P ≤ .08), whereas the serum concentrations of oxcarbazepine, zonisamide, and levetiracetam were unchanged (.06 ≤ P ≤ .90). The largest reduction in serum concentration was found for clobazam: mean reduction after 12 weeks was 1.5 µmol/L (34%). Percent change in serum concentration after 4 and 12 weeks of all drugs analyzed was -10.5% (95% confidence interval [CI] -14.1 to -6.8; n = 60; P < .001) and -13.5% (95% CI -18.8 to -8.3; n = 56; P < .001), respectively. Percent change in serum concentration of AEDs was not significantly correlated to percent change in seizure frequency after 12 weeks of dietary treatment (r = .14, P = .33, n = 53) but negatively correlated to urine ketosis (r = -.43; P = .003; n = 46). SIGNIFICANCE: A reduction in AED serum concentrations may counteract a seizure-reducing effect of the diet, and in patients without such an effect, it may cause seizure aggravation. Thus, we recommend that clinicians who are treating patients with ketogenic diets monitor serum concentrations of the concomitant AEDs.

Effects of Thylakoid-Rich Spinach Extract on the Pharmacokinetics of Drugs in Rats.

Thylakoid-rich spinach extract is being used as dietary weight-loss supplements in Japan. A recent rat study has suggested that intake of thylakoid-rich spinach extract with dietary oil inhibits dietary fat absorption via binding to bile acids, which promotes excretion of bile acids in feces. While, we confirmed that a serving size of thylakoid-rich spinach extract contains a large amount of calcium (130 mg/5 g). Therefore, using rats, we evaluated whether one-time ingestion of thylakoid-rich spinach extract affects the gastrointestinal absorption of water-insoluble drugs, such as griseofulvin (GF) and indomethacin (IM), or ciprofloxacin (CPFX) that chelate with polyvalent metal cations. Pretreatment of the rats with thylakoid-rich spinach extract (100 or 300 mg/kg) for 15 min prior to oral administration of GF (50 mg/kg) or IM (10 mg/kg) did not significantly alter the pharmacokinetic properties of either drug. Meanwhile, co-administration of thylakoid-rich spinach extract (500 mg/kg) and CPFX (20 mg/kg) significantly reduced the peak plasma concentration and the area under the plasma concentration-time curve of CPFX to 25 and 40%, respectively in rats. In vitro studies demonstrated that when a mixture of thylakoid-rich spinach extract and CPFX was centrifuged, there was a significant reduction in the supernatant concentration of CPFX relative to the control. When the experiment was repeated in the presence of ethylenediaminetetraacetic acid, the concentration of CPFX was unchanged. These results suggest that the intake of thylakoid-rich spinach extract may reduce the absorption of drugs that form a chelate with polyvalent metal cations, such as CPFX.

Marked change in blood tacrolimus concentration levels due to grapefruit in a renal transplant patient.

WHAT IS KNOWN AND OBJECTIVE: Reveal the current status of grapefruit in the Chinese medical environment. CASE DESCRIPTION: An approximately 2-fold increase in blood tacrolimus concentration was observed on day 9 in the hospital despite no change in dose. The only possible cause is that the patient had consumed grapefruit during hospitalization, which is often mistakenly considered to be a fruit belonging to the West and uncommon in the medical environment in China. WHAT IS NEW AND CONCLUSION: This is the first report of grapefruit-induced blood tacrolimus concentration change. Chinese medical practitioners should re-evaluate the impact of grapefruit and food-drug interactions caused by it.

PBPK Absorption Modeling of Food Effect and Bioequivalence in Fed State for Two Formulations with Crystalline and Amorphous Forms of BCS 2 Class Drug in Generic Drug Development.

Prediction of the effect of food on drug's pharmacokinetics using modeling and simulation could cause difficulties due to complex in vivo processes. A generic formulation with amorphous form of BCS 2 class drug substance was developed and compared in vitro and in vivo to the reference drug product with drug substance in crystalline form. In order to approve generic formulation, some regulatory agencies are requesting to perform bioequivalence (BE) studies also in fed state. Food can have various effects on drug dissolution and absorption, depending also on drug's properties. A physiologically based pharmacokinetic (PBPK) absorption model was built in GastroPlus™ to predict the food effect on generic and reference formulation and to predict the fed BE study outcome. During model development, we were searching for model inputs that impact and describe in vivo behavior of amorphous and crystalline forms of active pharmaceutical ingredient (API) in fast and fed conditions. The developed model was able to predict the food effect with up to 10% prediction error (PE). Performed virtual BE trials confirmed the BE of drug products in fed state. Our model was able to capture the difference between the two drug products containing different forms of API (amorphous and crystalline) and predict the food effect on both formulations.

Mini-Review: Drug-food interactions of commonly available juices of Pakistan.

Medicines are often consumed concurrently with food; sometimes to improve its absorption and efficacy. However, certain foods may modify the function of drug metabolizing enzymes or transport mechanisms that are crucial determinants of systemic drug availability. Extensive work has been reported on certain juices like grapefruit that affects the bioavailability of more than 60 medications. However, relatively less work has been reported on certain other commonly used fruit juices, especially in Pakistan, such as mango, strawberry, apple, banana, pomegranate and grape etc. Present review has taken an account of the current work done in this area.

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State.

Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma Cmax variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions.

Screening of furanocoumarin derivatives as cytochrome P450 3A4 inhibitors in citrus.

WHAT IS KNOWN AND OBJECTIVE: Furanocoumarins, such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB), isolated from grapefruit juice are clinically active constituents capable of inhibiting cytochrome P450 3A4. Furanocoumarins are also found in hassaku, pummelo and daidai. Several types of hybrid citrus fruits have recently been developed, and these may also contain furanocoumarins because they were produced by cross-breeding pummelo, daidai and other citrus fruits. In this study, we quantified BG and DHB levels in the flesh and peel of hybrid citrus fruits. METHODS: Extracts from flesh and peel were diluted with acetonitrile and analysed using high-performance liquid chromatography. RESULTS AND DISCUSSION: For flesh extracts, lime juice (24.13 µg/mL) contained a greater amount of BG than grapefruit juice (13.61 µg/mL). Lime (13.21 µg/mL) and sour orange (8.08 µg/mL) juices also contained greater amounts of DHB than grapefruit juice (7.54 µg/mL). For peel extracts, lime (1749.15 µg/g), Citrus kawachibankan (308.13 µg/g), lemon (203.44 µg/g) and sour orange (161.95 µg/g) contained greater amounts of BG than grapefruit (white) (78.80 µg/g). The hybrid sweetie (Citrus maxima × Citrus paradise; 173.32 µg/g) contained a greater amount of DHB than grapefruit (white) (85.27 µg/g). WHAT IS NEW AND CONCLUSION: The lime flesh and the sweetie peel contained the greatest amounts of furanocoumarins. Thus, caution is required during the simultaneous use of drugs metabolized by cytochrome P450 3A4 and consumption of these citrus fruits.

Physiological Considerations and In Vitro Strategies for Evaluating the Influence of Food on Drug Release from Extended-Release Formulations.

Food effects on oral drug bioavailability are a consequence of the complex interplay between drug, formulation and human gastrointestinal (GI) physiology. Accordingly, the prediction of the direction and the extent of food effects is often difficult. With respect to novel formulations, biorelevant in vitro methods can be extremely powerful tools to simulate the effect of food-induced changes on the physiological GI conditions on drug release and absorption. However, the selection of suitable in vitro methods should be based on a thorough understanding not only of human GI physiology but also of the drug and formulation properties. This review focuses on in vitro methods that can be applied to evaluate the effect of food intake on drug release from extended release (ER) products during preclinical formulation development. With the aid of different examples, it will be demonstrated that the combined and targeted use of various biorelevant in vitro methods can be extremely useful for understanding drug release from ER products in the fed state and to be able to forecast formulation-associated risks such as dose dumping in early stages of formulation development.

Preparation and Optimization of Rivaroxaban by Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Enhanced Oral Bioavailability and No Food Effect.

In this paper, a novel self-nanoemulsifying drug delivery system (SNEDDS) was used to improve the oral bioavailability in fasted state and diminish the food effect for rivaroxaban. Oil, surfactant, and co-surfactant were selected by saturated solubility study. IPM, Tween80, and 1,2-propanediol were finally selected as oil, surfactant, and co-surfactant, respectively. The pseudo-ternary-phase diagram was utilized to optimize the preliminary composition of SNEDDS formulation. The optimized rivaroxaban-SNEDDS formulation was selected by central composite design (CCD) of response surface methodology. Optimized SNEDDS formulation was evaluated for drug content, self-emulsifying time, droplet size, zeta potential, polydispersity index, Fourier transform-infrared (FTIR) spectroscopy, and transmission electron microscope (TEM). The drug dissolution profile compared to the commercial formulation Xarelto® (20 mg rivaroxaban) was determined in four different media (pH 1.2HCl, pH 4.5NaAc-HAc, pH 6.8PBS, and water). The result indicated that the SNEDDS formulation had successfully increased the drug solubility in four different media. A HPLC-MS method that indicated a high sensitivity, strong attribute, and high accuracy characteristic was built to measure the drug concentration in plasma. The fast/fed in vivo pharmacokinetics studies of SNEDDS formulation and Xarelto® were carried out in adult beagle dog, rivaroxaban with no food effect was achieved in SNEDDS formulation compared with Xarelto® in fed state. The result suggested that SNEDDS formulation in this study is useful to increase the oral bioavailability and diminish the food effect in fasted state.

Effect of Coadministered Water on the In Vivo Performance of Oral Formulations Containing N-Acetylcysteine: An In Vitro Approach Using the Dynamic Open Flow-Through Test Apparatus.

The drug plasma profile after oral administration of immediate release dosage forms can be affected by the human gastrointestinal physiology, the formulation, and the drug itself. In this work, we investigated the in vivo and in vitro performance of two formulations (granules vs. tablet) containing the highly soluble drug N-Acetylcysteine (BCS class I). Thereby, special attention was paid to the effect of the dosage form and the coadministration of water on drug release. Interestingly, the in vivo results from a pharmacokinetic study with 11 healthy volunteers indicated that the drug plasma concentrations were comparable for the tablet given with water as well as for the granules given with and without water. In order to mechanistically understand this outcome, we used a biorelevant dissolution test device, the dynamic open flow-through test apparatus. With the aid of this test apparatus, we were able to simulate biorelevant parameters, such as gastric emptying, hydrodynamic flow as well as physical stress. By this, it was possible to mimic the intake conditions of the clinical trial (i.e., drug intake with and without water). Whereas the experiments in the USP paddle apparatus revealed differences between the two formulations, we could not observe significant differences in the release profiles of the two formulations by using the dynamic open flow-through test apparatus. Even by considering the different intake conditions, drug release was slow and amounted to around 30% until simulated gastric emptying. These results suggest that dissolution was irrespective of coadministered water and the formulation. Despite the high aqueous solubility of N-Acetylcysteine, the limiting factor for drug release was the slow dissolution rate in relation to the gastric emptying rate under simulated gastric conditions. Thus, in case of administration together with water, large amounts of the drug are still present in the stomach even after complete gastric emptying of the water. Consequently, the absorption of the drug is largely controlled by the nature of gastric emptying of the remaining drug. The data of this study indicated that the water emptying kinetics are only determining drug absorption if drug release is rapid enough. If this is not the case, physiological mechanisms, such as the migrating motor complex, play an important role for oral drug delivery.

Inhibition of Breast Cancer Resistance Protein and Multidrug Resistance Associated Protein 2 by Natural Compounds and Their Derivatives.

The food and dietary supplements we consume contain a wide variety of plant secondary metabolites and other compounds, which, like drugs, can be absorbed, metabolized, distributed, and excreted from the body. In the intestine, these compounds can interact with transport proteins such as the multidrug resistance associated protein 2 (MRP2, ABCC2) and the breast cancer resistance protein (BCRP, ABCG2) that regulate the absorption of drugs and other compounds. Inhibition of these transporters by dietary components could lead to increased exposure and adverse effects of concomitantly administered drugs. Therefore, we screened a library of 124 natural compounds and their derivatives using the vesicular transport assay to evaluate their inhibitory potential on MRP2 and BCRP. Of the library compounds, 36% were identified as BCRP inhibitors, whereas the number was only 3.2% for MRP2. BCRP inhibitors are described by higher molecular weight, number of rings, aromaticity, and LogD7.4 than noninhibitors. IC50 values were measured for six dual inhibitors, among which three novel inhibitors, gossypin, nordihydroguaiaretic acid, and octyl gallate, were identified. Our results confirm that flavonoids are avid inhibitors of BCRP, and flavones and flavonols appear to be important subclasses of flavonoids for this inhibition. The strong inhibition of BCRP transport by some compounds suggests that their presence at high levels in the diet could cause food-drug interactions, but this seems to be a minor cause of concern for MRP2.

Simulating Different Dosing Scenarios for a Child-Appropriate Valproate ER Formulation in a New Pediatric Two-Stage Dissolution Model.

Predictive in vitro test methods addressing the parameters relevant to drug release in the pediatric gastrointestinal tract could be an appropriate means for reducing the number of in vivo studies in children. However, dissolution models addressing the particular features of pediatric gastrointestinal physiology and typical pediatric dosing scenarios have not yet been described. The objective of the present study was to combine the knowledge on common vehicle types and properties and current information on pediatric gastrointestinal physiology to design a dissolution model that enables a biorelevant simulation of the gastrointestinal conditions in young children. The novel dissolution setup consists of a miniaturized dissolution system allowing the use of small fluid volumes, physiological bicarbonate-based test media, and a proper pH control during the experiment using a pHysio-stat® device. Following design and assembly of the novel in vitro setup, a set of experiments screening in vitro drug release from a valproate-extended release formulation under typical dosing conditions in infants was performed. In vitro drug release profiles indicated a controlled drug release of the test product over 12 h and were in good agreement with information given in the Summary of Product Characteristics and the Patient Information Leaflet, as well as with results from an in vivo food effect study performed with the same product and reported in the literature. The new dissolution setup thus represents a promising in vitro screening tool in the development of pediatric dosage forms and may help to reduce the number of pharmacokinetic studies in children.

Non-vitamin K antagonist oral anticoagulants and antiphospholipid syndrome.

The current treatment of thrombotic APS patients includes long-term anticoagulation with oral vitamin K antagonists (VKAs), with warfarin being the one most commonly used. However, the use of VKAs can be challenging, especially in patients with APS. VKAs monitoring in patients with aPL is complicated by the heterogeneous responsiveness to LAs of reagents used in the International Normalized Ratio test, potentially resulting in instability of anticoagulation. For decades, VKAs were the only available oral anticoagulants. However, non-VKA oral anticoagulants, including a direct thrombin inhibitor (dabigatran etexilate) and direct anti-Xa inhibitors (rivaroxaban, apixaban and edoxaban), are currently available. The use of these agents may represent a major step forward since, unlike VKAs, they have few reported drug interactions and they do not interact with food or alcohol intake, thereby resulting in more stable anticoagulant intensity. Most importantly, monitoring their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this review, we discuss the clinical and laboratory aspects of non-VKA oral anticoagulants, focusing on the available evidence regarding their use in patients with APS.

Increased bioavailability of celecoxib under fed versus fasted conditions is determined by postprandial bile secretion as demonstrated in a dynamic gastrointestinal model.

The objective of this study was to utilize physiologically relevant dynamic dissolution testing with the TNO intestinal model (TIM-1) in vitro gastrointestinal model to investigate the bioaccessibility of celecoxib. A single 200-mg dose of celecoxib was evaluated under average adult human physiological conditions simulated in the TIM-1 system. The in vitro data were compared with the clinically established pharmacokinetic data. When expressed as a percent of drug that progresses from the duodenum to the jejunum and ileum compartments (bioaccessible sites), the study demonstrated a 2-fold increase in the total bioaccessibility for celecoxib when co-administered with a high-fat meal as opposed to co-administration with a glass of water (fasted conditions). That increase in bioaccessibility was similar to a 1.2 to 1.6-fold increase in systemic exposure in adults and children following co-administration with a high-fat meal when compared to the exposure measured when celecoxib was co-administered with only water. Following that comparison, the flexibility of the TIM-1 system was used to more specifically investigate individual parameters of gastrointestinal conditions, such as the rate of bile secretion (emptying of the bile bladder) that accompanies high-fat meal consumption. We demonstrated that increased bile secretion after co-administration of a high-fat meal played a more important role in the increased celecoxib bioaccessibility than did the food matrix. This indicates that in humans without a bile bladder the exposure of celecoxib administered with food might be as low as under fasted state.

Inhibition of human aldehyde oxidase activity by diet-derived constituents: structural influence, enzyme-ligand interactions, and clinical relevance.

The mechanistic understanding of interactions between diet-derived substances and conventional medications in humans is nascent. Most investigations have examined cytochrome P450-mediated interactions. Interactions mediated by other phase I enzymes are understudied. Aldehyde oxidase (AO) is a phase I hydroxylase that is gaining recognition in drug design and development programs. Taken together, a panel of structurally diverse phytoconstituents (n = 24) was screened for inhibitors of the AO-mediated oxidation of the probe substrate O(6)-benzylguanine. Based on the estimated IC50 (<100 µM), 17 constituents were advanced for Ki determination. Three constituents were described best by a competitive inhibition model, whereas 14 constituents were described best by a mixed-mode model. The latter model consists of two Ki terms, Kis and Kii, which ranged from 0.26-73 and 0.80-120 µM, respectively. Molecular modeling was used to glean mechanistic insight into AO inhibition. Docking studies indicated that the tested constituents bound within the AO active site and elucidated key enzyme-inhibitor interactions. Quantitative structure-activity relationship modeling identified three structural descriptors that correlated with inhibition potency (r(2) = 0.85), providing a framework for developing in silico models to predict the AO inhibitory activity of a xenobiotic based solely on chemical structure. Finally, a simple static model was used to assess potential clinically relevant AO-mediated dietary substance-drug interactions. Epicatechin gallate and epigallocatechin gallate, prominent constituents in green tea, were predicted to have moderate to high risk. Further characterization of this uncharted type of interaction is warranted, including dynamic modeling and, potentially, clinical evaluation.

Pharmacokinetics, pharmacodynamics and food effect of LB30870, a novel direct thrombin inhibitor, after single oral doses in healthy men.

1. The safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of LB30870, a new selective thrombin inhibitor, were studied in 16 healthy men. 2. A double-blind, placebo-controlled single ascending dose study was done at oral doses of 5, 15, 30, 60, 120, and 240 mg under fasting conditions. An open, randomized, balanced cross-over food effect study was done at 60 mg dose. Plasma and urinary concentrations were measured up to 48 h post-dose. Coagulation and thrombin activity markers were measured at selected time points. 3. Cmax of LB30870 was at 1.3-3.0 h post-dose with a mean apparent terminal half-life (t1/2) of 2.8-4.1 h. AUC after doses above 15 mg appeared greater than dose-proportional. In fed state, AUC showed 80% reduction relative to fasting condition. 4. At doses 60 and 120 mg, peak activated partial thromboplastin time (aPTT) increased by 1.5- and 2-fold, respectively, from baseline. The aPTT and international normalized ratio (INR) were concentration-dependent, with less within-individual variability than ecarin clotting time (ECT), prothrombin time (PT), or thrombin time (TT). 5. Single oral doses of LB30870 up to 240 mg were well tolerated. The food effect must be overcome if LB30870 is to be used as an oral anti-coagulant.