PURPOSE OF REVIEW: Oral drug absorption after bariatric surgery is likely to be altered, but the impact of different bariatric surgery procedures on individual drugs is not uniform. The aim of this article is to describe factors influencing the bioavailability of orally administered drugs after bariatric surgery and to provide readers with practical recommendations for drug dosing. We also discuss the medications that may be harmful after bariatric surgery. RECENT FINDINGS: The fundamental factors for enteral drug absorption are the production of gastric acid; the preserved length of the intestine, i.e., the size of the absorption surface and/or the preserved enterohepatic circulation; and the length of common loop where food and drugs are mixed with digestive enzymes and bile acids. Bypassing of metabolizing enzymes or efflux pumps and changes in intestinal motility can also play an important role. Significant changes of drug absorption early after the anatomic alteration may also be gradually ameliorated due to gradual intestinal adaptation. The most affected drugs are those with low or variable bioavailability and those undergoing enterohepatic circulation. Attention should also be paid to oral drug formulations, especially in the early postoperative period, when immediate-release and liquid formulations are preferred. The changes in oral bioavailability are especially clinically meaningful in patients treated with drugs possessing narrow therapeutic index (e.g., oral anticoagulants, levothyroxine, and anticonvulsants) or in acute conditions (e.g., anti-infectives); nevertheless, it may also influence the therapeutic value of chronic therapy (e.g., antidepressants. antihypertensives, antiplatelets, statins, PPIs, contraceptives, and analgesics); therapeutic effect of chronic therapy is further influenced by pharmacokinetic alterations resulting from weight loss. Therapeutic drug monitoring, periodical clinical evaluation, and adequate dose adjustments are necessary. Due to safety reasons, patients should avoid oral bisphosphonates, regular use of non-steroidal anti-inflammatory drugs, and, if possible, corticosteroids after bariatric surgery.
- MeSH
- bariatrická chirurgie * metody MeSH
- biologická dostupnost MeSH
- gastrektomie MeSH
- hmotnostní úbytek MeSH
- lidé MeSH
- morbidní obezita * chirurgie MeSH
- žaludeční bypass * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
- MeSH
- aplikace orální MeSH
- biologická dostupnost MeSH
- dasatinib MeSH
- klinické křížové studie MeSH
- lidé MeSH
- omeprazol * farmakokinetika MeSH
- plocha pod křivkou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Oxime reactivators of acetylcholinesterase are commonly used to treat highly toxic organophosphate poisoning. They are effective nucleophiles that can restore the catalytic activity of acetylcholinesterase; however, their main limitation is the difficulty in crossing the blood-brain barrier (BBB) because of their strongly hydrophilic nature. Various approaches to overcome this limitation and enhance the bioavailability of oxime reactivators in the CNS have been evaluated; these include structural modifications, conjugation with molecules that have transporters in the BBB, bypassing the BBB through intranasal delivery, and inhibition of BBB efflux transporters. A promising approach is the use of nanoparticles (NPs) as the delivery systems. Studies using mesoporous silica nanomaterials, poly (L-lysine)-graft-poly(ethylene oxide) NPs, metallic organic frameworks, poly(lactic-co-glycolic acid) NPs, human serum albumin NPs, liposomes, solid lipid NPs, and cucurbiturils, have shown promising results. Some NPs are considered as nanoreactors for organophosphate detoxification; these combine bioscavengers with encapsulated oximes. This study provides an overview and critical discussion of the strategies used to enhance the bioavailability of oxime reactivators in the central nervous system.
- MeSH
- acetylcholinesterasa * MeSH
- biologická dostupnost MeSH
- biologický transport MeSH
- centrální nervový systém * MeSH
- hematoencefalická bariéra MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Cannabidiol (CBD) is the non-psychoactive component of the plant Cannabis sativa (L.) that has great anti-inflammatory benefits and wound healing effects. However, its high lipophilicity, chemical instability, and extensive metabolism impair its bioavailability and clinical use. Here, we report on the preparation of a human cornea substitute in vitro and validate this substitute for the evaluation of drug penetration. CBD nanoemulsion was developed and evaluated for stability and biological activity. The physicochemical properties of CBD nanoemulsion were maintained during storage for 90 days under room conditions. In the scratch assay, nanoformulation showed significantly ameliorated wound closure rates compared to the control and pure CBD. Due to the lower cytotoxicity of nanoformulated CBD, a higher anti-inflammatory activity was demonstrated. Neither nanoemulsion nor pure CBD can penetrate the cornea after the four-hour apical treatment. For nanoemulsion, 94 % of the initial amount of CBD remained in the apical compartment while only 54 % of the original amount of pure CBD was detected in the apical medium, and 7 % in the cornea, the rest was most likely metabolized. In summary, the nanoemulsion developed in this study enhanced the stability and biological activity of CBD.
- MeSH
- antiflogistika farmakologie MeSH
- biologická dostupnost MeSH
- hojení ran MeSH
- kanabidiol * chemie MeSH
- lidé MeSH
- rohovka MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Pyruvate kinase (PK) M2 activators ramp up glycolysis in cancer cells, leading to a reversal of the Warburg effect in cancer cells. A promising PKM2 activator molecule, IMID-2, developed by the National Institute of Pharmaceutical Education and Research-Ahmedabad showed promising anticancer activity against MCF-7 and COLO-205 cell lines, which represent breast and colon cancer. Its physicochemical properties, like solubility, ionization constant, partition coefficient and distribution constant, have already been established. Its metabolic pathway is also well established through in vitro and in vivo metabolite profiling and reported previously. In this study, we have evaluated the metabolic stability of IMID-2 using LC-MS/MS and investigated the safety aspect of the molecule through an acute oral toxicity study. In vivo studies in rats confirmed that the molecule is safe even at a dose level of 175 mg/kg. Furthermore, a pharmacokinetic study of IMID-2 was also carried out using LC-MS/MS to understand its absorption, distribution, metabolism, and excretion profile. The molecule was found to have promising bioavailability through the oral route. This research work is thus another step in the drug testing of this promising anticancer molecule. The molecule can be considered to be a potential anticancer lead based on the earlier report substantiated by current findings.
In this randomized, open-label, 2-part, 2 × 2 crossover, phase 1 study, the effect of a low-fat low-calorie (LFLC) meal on the relative bioavailability of a trametinib 2-mg tablet or dabrafenib 150-mg capsule was evaluated in healthy participants. Trametinib adjusted geometric mean ratios (90%CI) of fed : fasted for area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity were 0.76 (0.71-0.82) and 0.82 (0.77-0.88), respectively. For dabrafenib, the adjusted geometric mean ratios of AUC from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity (90%CI) for fed:fasted were 0.85 (0.79-0.91) and 0.86 (0.80-0.92), respectively. Consumption of an LFLC meal delayed trametinib and dabrafenib absorption, with an increase in time to maximum concentration of ≈15 and ≈30 minutes, respectively, compared to the fasted state. These findings indicate that consumption of an LFLC meal reduced the bioavailability and delayed the absorption of trametinib and dabrafenib, supporting current recommendations to administer both drugs in the fasting state; however, an occasional LFLC meal is unlikely to affect the pharmacokinetics of the drugs once steady state is reached and, by consequence, not likely to alter the overall intended efficacy.
OBJECTIVE: Insulin-like growth factors (IGFs) are involved in regulating growth and metabolism and increase insulin sensitivity, improve glucose metabolism, and are potentially related to gestational diabetes mellitus (GDM) and its complications for mothers and fetuses. DESIGN: This study aimed to assess serum levels and cord blood levels of IGF system components in pregnant women with (39 participants) and without GDM (22 participants). Blood samples were obtained at 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. Cord blood samples were obtained during delivery. Results between both groups as well as between single visits were statistically compared. RESULTS: Both IGF1 and IGF2 maternal serum levels did not differ between the GDM and non-GDM groups. However, levels of IGF-binding proteins (IGFBPs) were different. IGFBP4 levels were decreased during pregnancy and after delivery in women with GDM, while IGFBP7 levels were increased during pregnancy in women with GDM. Cord blood IGFBP3 and IGFBP7 levels were increased (p < 0.001 for IGFBP3, p = 0.003 for IGFBP7), while IGFBP4 levels were decreased (p < 0.001) in the GDM group compared with the non-GDM group. CONCLUSIONS: Although IGF levels did not differ, changes in their function level could still persist possibly because of the effects of the binding proteins, especially their promoting or inhibitory effects on IGFs. These results should be considered in interpretation of IGF levels.
- MeSH
- biologická dostupnost MeSH
- fetální krev metabolismus MeSH
- gestační diabetes * metabolismus MeSH
- inzulinová rezistence * MeSH
- lidé MeSH
- proteiny vázající insulinu podobné růstové faktory metabolismus MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Alginates have been widely explored due to their salient advantages of hydrophilicity, biocompatibility, mucoadhesive features, bioavailability, environmentally-benign properties, and cost-effectiveness. They are applied for designing micro- and nanosystems for controlled and targeted drug delivery and cancer therapy as alginate biopolymers find usage in encapsulating anticancer drugs to improve their bioavailability, sustained release, pharmacokinetics, and bio-clearance. Notably, these nanomaterials can be applied for photothermal, photodynamic, and chemodynamic therapy of cancers/tumors. Future explorations ought to be conducted to find novel alginate-based (nano)systems for targeted cancer therapy using advanced drug delivery techniques with benefits of non-invasiveness, patient compliance, and convenience of drug administration. Thus, some critical parameters such as mucosal permeability, stability in the gastrointestinal tract environment, and drug solubility ought to be considered. In addition, the comprehensive clinical translational studies along with the optimization of synthesis techniques still need to be addressed. Herein, we present an overview of the current state of knowledge and recent developments pertaining to the applications of alginate-based micro- and nanosystems for targeted cancer therapy based on controlled drug delivery, photothermal therapy, and chemodynamic/photodynamic therapy approaches, focusing on important challenges and future directions.
- MeSH
- algináty * MeSH
- biologická dostupnost MeSH
- léky s prodlouženým účinkem MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- rozpustnost MeSH
- systémy cílené aplikace léků metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The pharmaceutical industry has to tackle the explosion of high amounts of poorly soluble APIs. This phenomenon leads to numerous sophisticated solutions. These include the use of multifactorial data analysis identifying correlations between the components and dosage form properties, laboratory and production process parameters with respect to the API liberation Example of such API is bicalutamide. Improved liberation is achieved by particle size reduction. Laboratory batches, with different PSD of API, were filled into gelatinous capsules and consequently granulated for tablet compression. Comparative dissolution profiles with Casodex 150 mg (Astra Zeneca) were performed. The component analysis was used for the statistical evaluation of f1 and f2 factors and D(v,0.9) and D[4,3] parameters of PSD to identify optimal PSD values. Suitable PSD limits for API were statistically confirmed in laboratory and in commercial scale with respect to optimized tablet properties. The tablets were bioequivalent with originator (n = 20; 90% CI for ln AUC0-120: 99.8-111.9%; 90% CI for ln cmax: 101.1-112.9%). In conclusion, the micronisation of the API is still an efficient and inexpensive method improving the bioavailability, although there are more complicated and expensive methods available. Statistical multifactorial methods improved the safety and reproducibility of production.
- MeSH
- anilidy chemická syntéza metabolismus MeSH
- biologická dostupnost MeSH
- chemie farmaceutická metody MeSH
- multivariační analýza MeSH
- nitrily chemická syntéza metabolismus MeSH
- tablety MeSH
- terapeutická ekvivalence MeSH
- tosylové sloučeniny chemická syntéza metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
The use of solid oral dosage forms depends on the degree of bioavailability of the active pharmaceutical ingredient. The rate and extent of the drug released from the dosage form and subsequently dissolved in the gastrointestinal fluids greatly affects its fate in the human body. In vitro dissolution test may provide an in-depth understanding of a drug formulation's behaviour in vivo, as long as it sufficiently simulates relevant gastrointestinal conditions. Therefore, the development of in vitro gastrointestinal systems, which reflects advanced technology and knowledge about the human body, is receiving considerable attention. This article is focused on the biorelevant dynamic apparatuses and their sophisticated design, overcoming many limitations of conventional dissolution devices and allowing a better correlation with in vivo behaviour of solid oral dosage forms.
