Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats.
Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.
Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
Pinaki
P
Sengupta
Utpal
U
Nandi
Tapan Kumar
TK
Pal
D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004338:Drug Combinations; D005260:Female; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D000068557:Olmesartan Medoxomil; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001786:Blood Glucose; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D007093:Imidazoles; D013777:Tetrazoles; D045162:Thiazolidinediones; D000068557:Olmesartan Medoxomil; D000077205:Pioglitazone