Pharmacodynamic and Pharmacokinetic Drug Interaction Of Gliclazide and Olanzapine in Animal Models

Abstract

Studies were conducted in normal rats, alloxan induced diabetic rats and normal rabbits with oral administration of selected doses of gliclazide, olanzapine and their combination with adequate wash out periods in between treatments. Blood samples were collected from rats and rabbits at regular intervals of time and were analysed for glucose by GOD/POD method and for gliclazide by HPLC method. Glicazide produced hypoglycemia and antihyperglycemia in normal/diabetic rats with peak activity at 1h & 8h and 3h & 10 h respectively and in rabbits at 2 h. Therapeutic dose of olanzapine alone did not alter the normal blood glucose level and it did not alter the hypoglycemic response produced by gliclazide in combination. The same phenomenon observed in diabetic rats and rabbits also. There was no significant change in the serum levels and pharmacokinetic parameters of gliclazide when given in combination with olanzapine in normal rabbits. Hence it is concluded that single dose treatment with olanzapine has no influence on pharmacodynamics/ pharmacokinetics of gliclazide. Since the combination was found to be safe in two dissimilar species, the combination might be safe in humans also.Keywords:-Drug interactions, Gliclazide, Olanzapine, Pharmacodynamics and Pharmacokinetics. Introduction:Now a days use of more than one drug (Polypharmacy) is a common practice to treat the chronic disorders like diabetes mellitus, hypertension etc. Polypharmacy is quite common practice all over the world to treat single disorder and multiple disorders which occur simultaneously. In such a situation one drug may interact with other drug leading to drug drug interactions. These interactions are more serious with high risk disorders like diabetes, hypertension or high risk drugs like antidiabetic, antihypertensive, antiarrhythmic drugs etc.Diabetes mellitus is one such disorder which requires careful management of its therapy with respect to blood glucose levels. There are reports for the development of diabetes mellitus in patients with CNS disorders like depression and schizophrenia [1] [2]. In such situations there is every possibility for the use of multiple drug therapy i.e; anti diabetic drugs with drugs for the treatment of other associated disorders and these situations may lead to drug-drug interaction problems. Maintenance of normal blood glucose levels is essential in diabetes since a decrease in blood glucose levels (hypoglycemia) or increase in blood glucose levels (hyperglycemia) is unwanted phenomenon. Hence monitoring of anti diabetic drug therapy in presence of other drugs is very much needed in order to maintain the safety.There are several reports that prevalence of type II diabetes in people with schizophrenia may be 2-4times higher than general population

Influence of Efavirenz and Nevirapine on the Pharmacodynamics and Pharmacokinetics of Gliclazide in Rabbits

“…Our study revealed the safety profi le of efavirenz and nevirapine with respect to glucose-insulin homeostasis. These results are also consistent with the available literature [5,19,25,28] and our former preliminary study [4]. But in combination, efavirenz signifi cantly decreased the pharmacodynamic activity (hypoglycemic effect and insulin levels) of gliclazide and it confi rms the presence of potent interaction between efavirenz and gliclazide.…”

“…Although animal models can never replace the need for comprehensive studies in human subjects, their use can provide important insights to understand and to evaluate the mechanism of potent drug interactions. It is worth noting that several fi ndings have confi rmed the functional similarity of CYP forms in rabbits and humans apart from convenience in serial blood sampling design suggesting that the rabbit is a valuable in vivo model for the assessment of drug interactions [5,19,[25][26][27][28].…”

“…Enzyme induction can be due to (i) a drug affecting its own metabolism (autoinduction), (ii) co-medication(s) with induction capability, or (iii) both. Gliclazide is known to be metabolized by CYP2C9 primarily and partly by CYP3A4 [5,25,28]. Gliclazide is primarily eliminated via renal (60-70%) [21] while efavirenz is primarily eliminated through feces (16-61%) [22].…”

Effect of protease inhibitors (indinavir and ritonavir) on the pharmacokinetics of gliclazide in rabbits

“…Gliclazide is rapidly absorbed in all species (man, monkey, beagle, rabbit, and rat) with similar excretion in all species and inter-species variation in half-life. 5,27 Our results in rabbits showed that gliclazide produced peak concentration at 3 hours with no second peak, while in rat models 5,[8][9][10]20,21 and humans 28 a second peak is reported to be common due to the presence biliary excretion and enterohepatic cycling of gliclazide. According to Davis et al 29 the extent of mean enterohepatic recirculation observed in humans was consistent with animal data.…”

“…It is worth noting that several findings have confirmed the functional similarity of CYP3A forms in rabbits and humans, suggesting that the rabbit is a valuable in vivo model for the assessment of drug interaction occurring at the first pass of drugs ingested. 5,13,[17][18][19][20][21] Moreover, studies performed on rabbits, evaluating the pharmacokinetics of other drugs metabolized in humans via CYP3A4 pathway [22][23][24] have confirmed the usefulness of the rabbit model for such investigations. Based on these findings, and apart from convenience of serial blood sampling, we preferred rabbit as an animal model to perform the pharmacokinetic interaction studies.…”