SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Pharmacokinetics

693

We propose that highly processed foods share pharmacokinetic properties (e.g. concentrated dose, rapid rate of absorption) with drugs of abuse, due to the addition of fat and/or refined carbohydrates and the rapid rate the refined carbohydrates are absorbed into the system, indicated by glycemic load (GL). The current study provides preliminary evidence for the foods and food attributes implicated in addictive-like eating.

Concepts: Nutrition, Food, Drug addiction, Addiction, Pharmacokinetics, Carbohydrate, Glycemic index, Glycemic load

168

We investigated flexible liposomes as a potential oral drug delivery system. However, enhanced membrane fluidity and structural deformability may necessitate liposomal surface modification when facing the harsh environment of the gastrointestinal tract. In the present study, silica-coated flexible liposomes loaded with curcumin (CUR-SLs) having poor water solubility as a model drug were prepared by a thin-film method with homogenization, followed by the formation of a silica shell by the sol-gel process. We systematically investigated the physical properties, drug release behavior, pharmacodynamics, and bioavailability of CUR-SLs. CUR-SLs had a mean diameter of 157 nm and a polydispersity index of 0.14, while the apparent entrapment efficiency was 90.62%. Compared with curcumin-loaded flexible liposomes (CUR-FLs) without silica-coatings, CUR-SLs had significantly higher stability against artificial gastric fluid and showed more sustained drug release in artificial intestinal fluid as determined by in vitro release assays. The bioavailability of CUR-SLs and CUR-FLs was 7.76- and 2.35-fold higher, respectively, than that of curcumin suspensions. Silica coating markedly improved the stability of flexible liposomes, and CUR-SLs exhibited a 3.31-fold increase in bioavailability compared with CUR-FLs, indicating that silica-coated flexible liposomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability.

Concepts: Pharmacology, Sol-gel, Drugs, Membrane biology, Medicinal chemistry, Pharmacokinetics, Biopharmaceutics Classification System, Digestion

168

OBJECTIVES: To determine the mycophenolic acid pharmacokinetic profile early after transplant in Iranian kidney graft recipients. MATERIALS AND METHODS: A cross-sectional study was performed during 6 months in 31 patients who recently had kidney transplant and received fixed doses of mycophenolate mofetil (2 g/d). The plasma levels of mycophenolic acid were determined by high performance liquid chromatography. RESULTS: The mean first mycophenolic acid peak level was 10 ± 5 mg/L. The mean mycophenolic acid area under the curve was 26 ± 19 mgh/L and apparent clearance was 57 ± 55 L/h. The mycophenolic acid area under the curve values of only 8 patients (26%) were within the therapeutic range (30-60 mgh/L). The first, second, and third mycophenolic acid peak levels correlated significantly with mycophenolic acid area under the curve (P < .05). Mycophenolic acid concentration at 10 hours had the highest correlation with mycophenolic acid area under the curve (r=0.962; P < .05). No statistically significant differences were evident in the mean mycophenolic acid area under the curve between men and women. CONCLUSIONS: There was a high degree of variation between different patients in mycophenolic acid pharmacokinetics early after kidney transplant.

Concepts: Pharmacology, Statistics, Statistical significance, High performance liquid chromatography, Kidney transplantation, Pharmacokinetics, Mycophenolic acid, Mycophenolate mofetil

168

The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [(14)C]-PF-04971729 to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of PF-04971729 in humans was rapid with a T(max) at ~ 1.0 h. Of the total radioactivity excreted in feces and urine, unchanged PF-04971729 collectively accounted for ~ 35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites M4a, M4b and M4c (~39.3% of the dose in urine) of which M4c was the major regioisomer (~31.7% of the dose). The structure of M4a and M4c were confirmed to be PF-04971729-4-O-β- and -3-O-β-glucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl PF-04971729 (M2), which accounted for ~5.2% of the dose in excreta. In plasma, unchanged PF-04971729 and the corresponding 4-O-β- (M4a) and 3-O-β- (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2 and 24.1% of the circulating radioactivity. Overall, these data suggest that PF-04971729 is well absorbed in humans, and eliminated largely via glucuronidation.

Concepts: Alcohol, Metabolism, Nutrition, Cytochrome P450, Steroid, Pharmacokinetics, Carbohydrate, Excretion

164

MMilk thistle (Silybum marianum) extracts, one of the most widely used dietary supplements, contain a mixture of six major flavonolignans (silybin A, silybin B, isosilybin B, isosilybin A, silychristin, and silydianin) and other components. However, the pharmacokinetics of the free individual flavonolignans has only partially been investigated in humans. Further, antioxidant effects of the extract, which may underlie the basis of many therapeutic effects, have not been thoroughly assessed. The present study was to evaluate the pharmacokinetics of the six major flavonolignans in healthy volunteers receiving single doses either one(175 mg), two(350 mg), or three(525 mg) of milk thistle capsule(s) on three separate study visits. Additionally, the steady state pharmacokinetic parameters were determined after the subjects were administered one capsule thrice daily for 28 consecutive days. Our results demonstrated that all six flavonolignans were rapidly absorbed and eliminated. In order of abundance, the exposure to free flavonolignans was greatest for silybin A followed by silybin B, isosilybin B, isosilybin A, silychristin, and silydianin. The systemic exposure to these compounds appeared linear and dose-proportional. The disposition of flavonolignans was stereoselective, as evidenced by the apparent clearance of silybin B, which was significantly greater than silybin A, whereas the apparent clearance of isosilybin B was significantly lower than isosilybin A. The concentrations of urinary 8-epi-prostaglandin F2α, a commonly used biomarker of oxidative status in humans, were considerably decreased in study subjects after a 28-day exposure to the extract (1.3±0.9 versus 0.8±0.9 ng/mg creatinine), but failed to reach statistical significance (P=0.076).

Concepts: Therapeutic effect, Antioxidant, Pharmacokinetics, Silybum marianum, Milk thistle, Flavonolignan, Silibinin, Amanita phalloides

149

To develop a comprehensive computational framework to simulate tissue distribution of gold nanoparticles (AuNP) across several species.

Concepts: Nanoparticle, Nanotechnology, Gold, Distribution, Pharmacokinetics

145

Personalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The inter-individual variability in drug response upon drug administration is caused by the interplay between drug pharmacology and the patients' (patho)physiological status. Individual variations in (patho)physiological status may result from genetic polymorphisms, environmental factors (including current/past treatments), demographic characteristics, and disease related factors. Identification and quantification of predictors of inter-individual variability in drug pharmacology is necessary to achieve personalized medicine. Here, we highlight the potential of pharmacometabolomics in prospectively informing on the inter-individual differences in drug pharmacology, including both pharmacokinetic (PK) and pharmacodynamic (PD) processes, and thereby guiding drug selection and drug dosing. This review focusses on the pharmacometabolomics studies that have additional value on top of the conventional covariates in predicting drug PK. Additionally, employing pharmacometabolomics to predict drug PD is highlighted, and we suggest not only considering the endogenous metabolites as static variables but to include also drug dose and temporal changes in drug concentration in these studies. Although there are many endogenous metabolite biomarkers identified to predict PK and more often to predict PD, validation of these biomarkers in terms of specificity, sensitivity, reproducibility and clinical relevance is highly important. Furthermore, the application of these identified biomarkers in routine clinical practice deserves notable attention to truly personalize drug treatment in the near future.

Concepts: Scientific method, Pharmacology, Medicine, Prediction, Medicinal chemistry, Pharmacokinetics, Pharmacy, Pharmacodynamics

145

This study aimed to investigate the pharmacokinetics (PK), safety and tolerability of a single dose of ceftazidime-avibactam in pediatric patients.

Concepts: Pharmacology, Pharmacokinetics

89

To assess the pharmacokinetic properties of community-use formulations of naloxone for emergency treatment of opioid overdose.

Concepts: Pharmacology, Opioid, Morphine, Heroin, Naloxone, Route of administration, Pharmacokinetics, Drug overdose

80

Absorption of current rapid-acting insulins is too slow for patients with diabetes mellitus to achieve optimal postprandial glucose control. Faster-acting insulin aspart (faster aspart) is insulin aspart in a new formulation with faster early absorption. We compared the pharmacokinetic/pharmacodynamic properties of faster aspart and insulin aspart across a clinically relevant dose range.

Concepts: Nutrition, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Glucose, Diabetes mellitus type 1, Obesity, Pharmacokinetics