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

 

CHAPTER-1

Introduction

 

 

            In modern life today, numerous studies have demonstrated that many patients receive multiple drug therapy with recognized potential. Such interactions can increase the drug effect to the level of toxicity, or they can inhibit the drug effect and deprive the patient of therapeutic benefit. As the number of drugs in patient‟s therapeutic regimen increases, the greater is the risk of occurrence of drug interaction¹. It is known that the incidence of adverse drug reaction to drugs rise from 4.2% when five or fewer drugs are used to 45% when twenty or more drugs are used. This may lead to enhanced or diminished effect of concomitantly used drugs may be useful or harmful. The useful drug interaction is illustrated by synergistic combination of drugs such as antibiotics or anti neoplastic. Harmful drug interactions are, unfortunately, more numerous⁴.

 

Drug-drug interactions are of potential concern whenever a person takes two or more medications concurrently. Indeed, in a recent poll adults were asked what they would be “very concerned” about if they were to check into a hospital or other health care facility. The number one concern (61%) was being given the wrong medicine, but a close second at 58% was a negative interaction between multiple drugs⁵.

 

Drug interactions are often categories as;

1.      pharmacodynamic

2.      Pharmacokinetic in nature⁶.

 

It can be either beneficial or detrimental to patients⁶. In such cases it is needed to alter the dose and frequency of administration of one or all drugs, which are to be administered simultaneously.

 

            A pharmacodynamic drug interaction occur, two drugs have additive or antagonistic pharmacologic effects

 

            A pharmacokinetic drug interactionoccur,one drug affects the absorption, distribution, metabolism, or excretion of another .

 

Any type of drug interaction can result in adverse effects in some individuals⁵.When discussing drug interactions, the drug affected by the interaction is called the “object drug,” and the drug causing the interaction is called the “precipitant drug.”⁵

 

Multiple drug therapy assume importance in present day clinical practice, since newer molecules are invented every day and newer challenges face clinicians in managing either a single disease or simultaneously occurring different disease⁷.

 

Very often some life threatening adverse drug reactions also may be precipitated due to drug-drug interactions. ‘The NationalCenter for Health’ Statistics report that 19,250 people died of accidental poisoning in the U.S. in the year 2004 (8 deaths per 100,000 population). In 2008 testimony before a Senate subcommittee, Medical Epidemiologist Dr. Leonard J. Paulozzi of the ‘Centers for Disease Control and Prevention’ stated that in 2005 (the most recent year for which data was available) more than 22,000 American lives were lost due to overdoses and drug interaction, and the number is growing rapidly⁸.

Diabetes mellitus (sometimes called "sugar diabetes") is a condition that occurs when the body can't use glucose (a type of sugar) normally. Glucose is the main source of energy for the body's cells. The levels of glucose in the blood are controlled by a hormone called insulin, which is made by the pancreas. Insulin helps glucose enter the cells⁹.In diabetes, the pancreas does not make enough insulin (type 1 diabetes) or the body can't respond normally to the insulin that is made (type 2 diabetes). This causes glucose levels in the blood to rise, leading to symptoms such as increased urination, extreme thirst, and unexplained weight loss⁹.

There are three main types of diabetes mellitus.

1.      Type 1 diabetes mellitus or insulin dependent diabetes mellitus (IDDM).

2.      Type 2 diabetes mellitus or non insulin dependent diabetes mellitus (NIDDM).

3.      Gestational diabetes – high blood sugar level during pregnancy¹⁰.

 

            Among diabetics approximately 95% of patients have type II diabetes mellitus, whereas about 5% of patients have type I diabetes mellitus¹¹. The global prevalence of type II diabetes is expected to double in the period 2000-2025 and may reach a level of almost 300 million people¹².

 

            Unfortunately, diabetes has been associated with serious complications and premature death. The statistics are dramatic.

 

            Worldwide at least 171 million people have diabetes; this figure is likely to be more than double by 2030. Unfortunately, India has the largest number of diabetic patients in the world. The disease is such that it cannot be cured; only managed. Diabetes, which was once prevalent only among adults, is now found commonly in children due to change in lifestyle and imbalanced eating habits¹³.

 

The International Diabetes Federation recently published findings revealing that in 2007, the country with the largest numbers of people with diabetes is India (40.9 million), followed by China (39.8 million), the United States (19.2 million), Russia (9.6 million) and Germany (7.4 million).
Some other alarming diabetes statistics include the fact that there is one person in the world dying of diabetes every ten seconds.Also, there will be two new diabetic cases in the world being identified every ten seconds. And, what’s worse, these statistics also tell us that by the year 2025, there will be seven million new diabetic cases in the world¹³.

 

Insulin – dependent diabetes mellitus results from insulin deficiency caused by cell – mediated autoimmune destruction of pancreatic β-cells, and generally develops in the young. It accounts for approximately 10-15% of the diabetic population worldwide.

 

In contrast, Non-Insul34n dependent diabetes mellitus results from a variable combination of insulin resistance and insulin deficiency, and generally develops in adults¹⁵. Patients with diabetes mellitus are at risk for micro vascular and macro vascular complications that increase morbidity and mortality¹⁴.

 

In type 2 diabetes mellitus, minor complications such as hypoglycemia, hyperglycemia, ketoacidosis, and hyper-osmolar syndrome etc. can be seen frequently, while major complications such as heart disease, kidney disease, neuropathy, diseases of the eyes, peripheral vascular disease etc. can compromise readily in the diabetic patient¹⁵.

 

Various drugs have been extensively used for the treatment of type 2 diabetes since last long many years. The most commonly using antidiabetic drugs are sulfonylurea, thiazolidinediones, alpha glucosidase inhibitors, meglitinide, dipeptidyl peptidase 4 inhibitors (DPP-4) etc¹⁶.

 

      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 hyperglycemia^17.

Abraxane is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug.  Abraxane is classified as "plant alkaloid," a "taxane" and an "antimicrotubule agent."¹⁶ Abraxane is used to treat breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.  Prior therapy should have included an anthracycline chemotherapy unless clinically not appropriate. Non-small cell lung cancer¹⁸.

Nateglinide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It belongs to the meglitinide class of short-acting insulin secretagogues, which act by binding to β cells of the pancreas to stimulate insulin release¹⁹.

Repaglinide belongs to the meglitinide class of blood glucose-lowering drugs. Repaglinide lowers blood glucose by stimulating the release of insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion²⁰.

Diabetes and cancer are common diseases with tremendous impact on health worldwide. A large number of drugs are introduced every year, and new interactions between medications are increasingly reported. Multiple drug regimens carry the risk of adverse interactions²¹.

As these drugs share a common enzyme system of there metabolism,there may exist drug-drug interaction between these drugs on concominant administration.

However from the above mentioned drugs it has been confirmed that drug interactions reveals that, there are no report about the possible drug interaction between Abraxane and anti Diabetic agents like Nateglinide and Repaglinide.

Hence, in the present study the main objective is to understand drug-drug interaction that influence of abraxane administration along with the anti diabetic potency of Nateglinide and Repaglinide.