Molecular mechanism of action and pharmacokinetic properties of methotrexate.

Since its discovery in 1945, methotrexate has become a standard therapy for number of diseases, including oncological, inflammatory and pulmonary ones. Major physiological interactions of methotrexate include folate pathway, adenosine, prostaglandins, leukotrienes and cytokines. Methotrexate is used in treatment of pulmonary sarcoidosis as a second line therapy and is drug of choice in patients who are not candidates for corticosteroid therapy, with recommended starting weekly dose of 5-15 mg. Number of studies dealt with methotrexate use in rheumatoid arthritis and oncological patients. Authors are conducting research on oral methotrexate use and pharmacokinetics in chronic sarcoidosis patients and have performed literature research to better understand molecular mechanisms of methotrexate action as well as high level pharmacokinetic considerations. Polyglutamation of methotrexate affects its pharmacokinetic and pharmacodynamic properties and prolongs its effect. Bile excretion plays significant role due to extensive enterohepatic recirculation, although majority of methotrexate is excreted through urine. Better understanding of its pharmacokinetic properties in sarcoidosis patients warrant optimizing therapy when corticosteroids are contraindicated in these patients.

Potentials of human bile acids and their salts in pharmaceutical nano delivery and formulations adjuvants.

In the last decade, the attention of the scientific community has been focused on bile acids and their salts as systems for the transportation of drugs; specifically their role as carriers and integration into nanomedicine. Bile acids can play a critical role as drug carriers in the form of chemical conjugates, complexation, mixed micelles formation as well as stabilized bile acid liposomes (bilosomes). The unique molecular structure and interaction of these amphiphilic-steroidal compounds make them an interesting subject of research. This review is based on literature research in order to emphasize the importance of bile acids and their salts as absorption modulators in order to improve therapeutic potentials of low bioavailability drugs.

Docking-based preliminary study on the interactions of bile acids with drugs at the transporter level in intestinal bacteria.

OBJECTIVE: The aim of this study was to estimate the binding-affinities of different bile acids towards drug transporters in Lactobacillus acidophilus and Bifidobacterium longum in order to predict the influence of bile acids and probiotics interactions on drug pharmacokinetics. MATERIALS AND METHODS: In order to study interactions of bile acids with transporters of intestinal bacteria, molecular-docking step was performed, using SwissDock web-service. For the purpose of comparison, two natural bile acids, cholic acid (CA) and deoxycholic acid (DCA), and one semi-synthetic bile acid, 12-monoketocholic acid (MKC), were studied in parallel. The free-binding energy was used as the main criterion for ranking ligands. RESULTS: Studied bile acids exhibited different binding affinities towards bacterial transporters with MKC showing the most prominent effect. For the majority of studied transporters, the estimated affinities of bile acids decreased in the following order: MKC-CA-DCA. Namely, 38.7% of examined transport proteins gave the lowest free-binding energy with MKC. The weak inverse relationship between number of hydrogen bonds and estimated free-binding energies was revealed. CONCLUSIONS: The predominant effect of MKC for the majority of studied transport proteins suggests that keto group at carbon 12 of the steroid core has a significant influence on the properties of MKC and consequently, on interactions with membrane transporters. Present findings might have a role in the prediction of potential influence of bile acids and probiotics on drug pharmacokinetics.

Bioavailability and hypoglycemic activity of the semisynthetic bile acid salt, sodium 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate, in healthy and diabetic rats.

Previous studies in our laboratory have shown that the semisynthetic bile acid derivative, sodium 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate (MKC), has hypoglycemic activity. The aim of this study was to investigate the relationship between the pharmacokinetics and hypoglycemic activity of MKC in healthy and diabetic rats. Groups of healthy and alloxan-induced diabetic rats were dosed intravenously (i.v.) and orally with MKC (4 mg/kg). Blood samples were taken before administration of the dose and at 20, 40, 60, 80, 120, 150, 180, 210 and 240 minutes post-dose. MKC serum concentration was measured by HPLC, and pharmacokinetic parameters determined using the WinNonlin program. The absolute bioavailability of MKC was found to be low in healthy and diabetic rats (29 and 23% respectively) and was not significantly different between the two groups. Mean residence time (MRT), volume of distribution (Vd) and half-life (t1/2) of MKC after oral administration were significantly lower in diabetic than in healthy rats (21, 31 and 29% respectively). After the i.v. dose, the change in blood glucose concentration was not significant in either healthy or diabetic rats. After the oral dose, the decrease in blood glucose concentration was significant, reaching a maximum decrease from baseline of 24% in healthy rats and 15% in diabetic rats. The results suggest that a first-pass effect is crucial for the hypoglycemic activity of MKC, indicating that a metabolite of MKC and/or interference with metabolism and glucose transport is responsible.