A COMBINED MODEL FOR PREDICTING CYP3A4 CLINICAL NET DRUG-DRUG INTERACTION, BASED ON CYP3A4 INHIBITION - OBJECTIVES

 

Objectives

 

            A drug interaction is a situation in which a substance affects the activity of a drug, i.e.Drug-drug interactions are possible whenever a person takes two or more medications concurrently. There are a number of mechanisms by which drugs interact with each other, and most of them can be divided into two general categories: pharmacokinetic and pharmacodynamic interactions.

 

With pharmacokinetic drug interactions, one drug affects the absorption, distribution, metabolism, or excretion of another. When pharmacodynamic drug interactions occur, two drugs have additive or antagonistic pharmacologic effects. Either type of drug interaction can result in adverse effects in some individuals²².

 

Generally it has been found that the detrimental effects of drug interactions are more as compared to its beneficiary effects. In such cases it is needed to alter the dose and frequency of administration of one or all drugs to avoid possible hazards, which are to be administered simultaneously.

 

Diabetes is a polygenic disease characterized by abnormally high glucose levels in the blood; any of several metabolic disorders marked by excessive urination and persistent thirst²³.  Diabetes is always coinciding with serious complications and adverse effects.

 

The U.S. incidence of both diabetes mellitus and cancer is increasing. Approximately 1.6 million new cases of diabetes mellitus and 1.4 million of cancer are diagnosed every year. Large cohort studies show that pancreatic, colorectal, breast, hepatobiliary, bladder, and endometrial cancers occur more frequently in people with type 2 diabetes. Potential reasons behind this association include common causality (shared risk factors), hyperglycemia, and other metabolic abnormalities of type 2 diabetes that cause cancer, and cancer that causes hyperglycemia²⁴. For diabetes lifelong therapy is needed to control it. In this there is an every possibility of developing secondary infections and cancer diseases.

 

            Amongst many possible side effects and complications, Epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer, Type 2 diabetes and cancer share many risk factors, but potential biologic links between the two diseases are incompletely understood. Moreover, evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer²⁵, so use of anti cancer drugs become necessary to co administer with anti diabetic drug therapy. Hence, there may be a great chance of occurring drug-drug interactions while using such multi drug therapy regimen together. There are clear indications that anti neoplastic agents interfere with cytochrome P450 enzyme system when they are used concomitantly.

 

The isoenzyme CYP3A4 and CYP2C9 are responsible for the metabolism of Nateglinide²⁶, while Repaglinide is metabolized through isoenzyme CYP3A4 and CYP2C8²⁷. Abraxane also get metabolized by the above mentioned isoenzymes i.e. CYP3A4,CYP2C8 and CYP2C9 is an inducer or inhibitor of above mentioned isoenzyme²⁸.

 

Hence, keeping the possibility of interactions between Abraxane, Nateglinide and Repaglinide in view, the present study was planned with the following objectives.

 

1.      To study the influence of Abraxane on the hypoglycemic activity of Nateglinide and Repaglinide in healthy experimental animals like rats and rabbits.

 

2.      To study the influence of repeated administration of Abraxane on the antidiabetic activity of Nateglinide and Repaglinide in a diabetic rats. Diabetes was induced by Streptozotocin pretreatment.

 

3. To suggest the alteration in the dose and frequency of administration of Nateglinide and Repaglinide when they are used anti neoplastic agent like Abraxane.