In this study, the interaction of selected pharmaceutical excipients on the function of P-glycoprotein (P-gp) and activity of 6 cytochrome P450 (CYP) isoforms were computationally investigated. At binding free energy cut-off value of −5.0 kcal/mol, the result showed possible modulatory or inhibitory effect by cethyl alcohol on CPY3A4 and P-gp; cetyltrimethyl-ammonium bromide (CTAB) on CYP1A2 and P-gp; dibutyl sebacate on CYP2C9, CYP2E1, and P-gp; sodium caprylate on CYP1A2 and CYP3A4; while most of the tested excipients have good interaction with the cytochromes and P-gp. The predicted pharmacokinetics provided possible inhibitors of the CYPs and P-gp and suggested that aspartame and acetyl tributyl citrate may not permeate blood–brain barrier and not act as P-gp substrates. Target prediction for CTAB showed 100% and 35% probability of target to dynamin-1 (UniProt ID: Q05193) and histamine H3 receptor (UniProt ID: Q9Y5N1), respectively, whereas tricaprylin showed 40% probability of target to 5 Protein kinase C (UniProt IDs: P17252, Q02156, Q04759, P24723, and P05129). This study shows that synergistic effect of some excipients present in a drug formulation and multiple drugs administration is possible through modulation of CYPs activities and P-gp function, and this is crucial for consideration to mitigate toxicity in pediatric and adult populations.
Diabetes mellitus has been a metabolic disorder characterized by interferences in the breakdown of carbohydrate, lipid, and protein as a result of insulin deficiency. Great efforts are ongoing in understanding and management of diabetes, and disease related complication. In this work, an attempt was made to study the hematological and hypoglycemic effects of Annona muricata ripe fruits pulp in Streptozotocin (STZ)-induced diabetic rats and validates its traditional claim. The forty-eight (48) Albino rat were divided into six groups which include normal, tests and controls. The diabetes–induced rats were fed orally with A. muricata ripe fruits pulp extract in concentrations of 750 mg, 1000 mg, and 2000 mg respectively. The results showed that the extract caused fasting blood sugar glucose levels to remarkably reduced to near normal. Hematological studies revealed that there were improvements in the hematological indices tested groups when compare with diabetes normal group. The molecular docking results indicate that the phytochemicals in A. muricata ripe fruit pulp have more affinity for aldose reductase followed by alpha-amylase and then alpha-glucosidase, and that montecristin, epoxymurin-A, dicaffeoylquinic acid, and kaempferol 3-O-rutinoside show higher affinity to the three targets than acarbose. These results indicate that ripe fruits pulp of A. muricata possesses a strong hypoglycemic effect in STZ–induced diabetic rats, thus supporting its traditional use in the management of diabetes mellitus.
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