A COMBINED MODEL FOR PREDICTING CYP3A4 CLINICAL NET DRUG-DRUG INTERACTION, BASED ON CYP3A4 INHIBITION - REVIEW OF LITERATURE

review of literature

 

A clinically relevant drug-drug interaction (DDI) is defined as an alteration in the effectiveness or toxicity of one medication by the administration of either another medicine or a substance administered for medical purposes-a distinction made to distinguish these from drug-food interactions29. Drug interactions may be either beneficial or detrimental, but harmful effects are usually predominated.

 

Literature survey was carried out on the proposed research work by referring various scientific Research journals, Internet, Helinet facilities and science direct. Upon through survey of literature it was revealed that, the incidence of type 2 diabetes mellitus is increasing day by day disappointingly30.

 

The metabolism of Abraxane (paclitaxel) is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering Abraxane concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungal,erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A431.

 

Diabetes is defined as a disorder exhibiting hyperglycemia caused by deficient insulin action, which is determined by both the capacity to secrete insulin from pancreatic β-cells and insulin action in peripheral insulin-sensitive tissue such as muscle and liver. According to its pathophysiology, diabetes is basically classified into two categories: type 1 and type 2. Impaired insulin secretion is the major cause of type 1 diabetes, while insulin resistance plays an important role in the pathophysiology of type 2 diabetes.

 

Diabetes is a condition for which there is no cure. It affects more than 20million Americans every year, and though it can be managed, there are side effects that stem from it32. Diabetes can be associated with many serious health problems and complications such as secondary infections. Diabetes and cancer are common diseases with tremendous impact on health worldwide.

 

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 habits33.

 

Using data from an ongoing government health survey, researchers found that Asian Americans had consistently higher rates of type 2 diabetes than white Americans from 1997 to 2008.What's more, diabetes rates rose over time for both racial groups, reaching 8 percent among Asian adults and 6 percent among whites Americans34.

 

India is being called the diabetic hub of the world, with around 30 million diabetic patients. As per the International Diabetic Federation report, by 2030 over 8.4 percent of the Indian adult population will suffer from diabetes35.

 

In 2012, it is estimated that among U.S. women there will be226,870new cases of invasive breast cancer (includes new cases of primary breast cancer among survivors, but not recurrence of original breast cancer among survivors).14 63,300 new cases of in situ breast cancer (includes ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), of those, about 85 percent will be DCIS). DCIS is a non-invasive breast cancer and LCIS is a condition that increases the risk of invasive breast cancer. Learn more about DCIS and LCIS.39,510breast cancer deaths36. Breast cancerin men is rare, but it does happen. In 2012, it is estimated that among U.S. men there will be 2,190 new cases of breast cancer. 410 breast cancer deaths37.

 

From the literature survey it reveals that the incidence of type II diabetes mellitus is increasing day by day disappointingly. It is a serious disorder with significant public health implications38.

 

Antidiabetic drugs such as Sulfonylureas (Glibenclamide, Gliclazide, and Glimipride), Thiazolidinediones like Repaglinide, Repaglinide and Meglitinide like Nateglinide are the most commonly used for the treatment of type II diabetes39.

 

Biotransformation of lipophilic xenobiotics compounds into more hydrophilic metabolites occurs through reactions that are classified as either phase-I or phase-II.

 

Phase-I reactions, usually through oxidation or hydrolysis, introduce or expose polar functional groups on the compound, rendering the drugs more hydrophilic.

 

Phase-II reaction involves conjugation with endogenous agents like glucuronic acid, sulphate, glutathione, or amino acids onto functional groups on the compound or metabolite, resulting in excretion in the urine or feces40. One of the most important and well-characterised enzyme systems responsible for phase-I drug metabolism are the cytochrome P450s. because of their prominent role in drug metabolism, the P450s are often involved in drug interaction.

 

The story of cytochrome P-450, like a tree, has many roots and branches. Its roots go back to many beginnings. Rapid development in the field of Molecular Biology greatly expanded the ability to detect, identify, and produce forms of cytochrome P-450 that are expressed in extremely small amount in the tissue. And finally the researchers explained that one common way of metabolising drugs involves the alteration of functional groups on the parent molecule e.g., oxidation via the cytochrome P-450 enzymes41.

 

The role of cytochrome P-450 in hepatic microsomal drug oxidation42:

 

The schematic representation of its role is given below;

 Three families of CYP P450s are primarily responsible for xenobiotics metabolism: CYP1, CYP2, and CYP3. These three families of CYP P450s account for approximately 70% of total CYP P450s in the human liver with approximately 50% being comprised of members of the CYP3A and CYP2C subfamilies about 30% and 20% espectively43. In addition they have been further divided into various sub families, which are denoted by A, B, C, D and E.  These cytochrome P-450 enzymes are designated by the letters “CYP” followed by a numeral, a letter and another numeral e.g., CYP2D644. The cytochrome P450(CYP) enzyme system consists of a super family of hemoproteins that catalyze the oxidative metabolism of a wide variety of exogenous chemicals including drugs, carcinogens, toxins and endogenous compounds such as steroids, fatty acidsand prostaglandins44.

 

As for their role in drug metabolism, CYP3A participate in the metabolism of approximately 50% of all drugs with CYP2D6 contributing to approximately 25%, CYP2C9 to approximately 15%, and CYP1A2 to approximately 5%45. Thus, these four P-450s participate in the metabolism of 95% of all the drugs.   

 

 

            Approaches to Drug Therapy in Diabetes Mellitus46

 

1) Improve Insulin Availability

 

i)                    Exogenous Insulin

 

              (a) Short acting Insulin (b) Intermediate acting insulin (c) Long acting insulin

 ii) Sulfonylurea

 

             (a) First generation: a. Tolbutamide, b. Chlorpropamide

             (b) Second generation: a. Glipizide, b. Glibenclamide, c. Gliclazide,

 

ii)                 Meglitinide analogues

 

             (a) Repaglinide (b) Nateglinide.

2) Overcome Insulin resistance

 

i)                    Biguanides

 

           (a) Phenformin (b) Metformin.

 

ii)                 Thiazolidinediones

 

(a) Repaglinide (b) Rosiglitazone.


 

 

NATEGLINIDE:

 

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 release47.

 

Structure:

 

Chemical Formula:

C19H27NO3 

 

Chemical Name:

(2S)-3-phenyl-2-[(4-propan-2-ylcyclohexanecarbonyl) amino] propanoic acid.

 

Mechanism of action48:

Nateglinide is effective in a treatment for type 2 diabetes mellitus but should not be used in type 1. Because it has a rapid onset and a short duration of action, it is also effective in controlling postprandial hyperglycemia with a minimal risk of hypoglycemia or other adverse. Nateglinide is an "insulotrophic" agent - Nateglinide lowers blood glucose by stimulating insulin production from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.

 

Nateglinide stimulates pancreatic insulin secretion within 20 minutes of administration. The extent of insulin secretion is glucose dependent and diminishes at low glucose levels; once blood glucose normalizes, the effects of the drug cease. Glycosylated hemoglobin (HbA1c) concentrations decrease during therapy with Nateglinide.

 

Pharmacokinetics48:

Absorption:

            Following oral administration immediately prior to a meal, Nateglinide is rapidly absorbed with mean peak plasma drug concentrations (Cmax) generally occurring within 1 hour (Tmax) after dosing. Nateglinide demonstrate a linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and Cmax. Tmax was also found to be independent of dose in this patient population. Absolute bioavailability is estimated to be approximately 73%. When given with or after meals, the extent of Nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in Cmax and a delay in time to peak plasma concentration (Tmax). 

 
Distribution:

The steady-state volume of distribution of Nateglinide is estimated to be approximately 10 liters in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α1 acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1-10 μg/mL.

 

Metabolism:

Nateglinide is metabolized by the liver, and the metabolites are excreted in the urine. It is metabolized by the mixed-function oxidase system prior to elimination. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than Nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound Nateglinide. The plasma half-life of Nateglinide following a single oral dose is approximately < 1.5 h.

 

            In-vitro data demonstrate that Nateglinide is predominantly metabolized by cytochrome P450 isoenzyme CYP2C9 (70%) and CYP3A4 (30%).

 
Excretion:

Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within 6 hrs after dosing, approximately 75% of administered Nateglinide was recovered in the urine, with an additional 10% eliminated in the feces. Approximately 16% of the Nateglinide was excreted in the urine as parent compound. The average rate of elimination half-life is approximately 1.5 hrs. Consistent with this short elimination half-life, there was no apparent accumulation of Nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.

 

Interactions of Nateglinide:

From the literature survey, it has been revealed that several researches regarding drug-drug interactions had been carried out by many research scholars as described below.

1.      Niemi M et al has reported that Rifampicin decreased the mean AUC of nateglinide by 24% and shortened its half-life (t(1/2)) from 1.6 to 1.3 hr. However, the peak plasma nateglinide concentration (Cmax) remained unchanged. The AUC of the M7 metabolite of nateglinide was decreased by 19% and its t(1/2) was shortened from 2.1 to 1.6 hrs by Rifampicin. Rifampicin modestly decreased the plasma concentrations of nateglinide probably by inducing its oxidative biotransformation. In some patients, rifampicin may reduce the blood glucose-lowering effect of nateglinide49.

2.      Terada T et al has suggested that Nateglinide exhibited a potent inhibitory effect on [14C] glycylsarcosine uptake by the human colon adenocarcinoma cell line Caco-2 and rat PEPT-transfectants. Kinetic analysis revealed that these inhibitory effects were noncompetitive. In conclusion, nateglinide inhibit the transport activity of PEPT1 and PEPT2, although nateglinide itself is not transported by these transporters50.

3.      Mikko MD et al has reported that Fluconazole raised the total area under the plasma concentration–time curve from time 0 to infinity of nateglinide by 48% and prolonged its half-life from 1.6 to 1.9 hrs (P < .05). The peak plasma concentration of the M7 metabolite of nateglinide was reduced by 34% by fluconazole (P < .001), and its half-life was prolonged from 2.2 to 3.5 hrs (P < .05). Fluconazole raised the plasma concentrations and reduced the systemic elimination of nateglinide probably by inhibiting its cytochrome P4502C9–mediated biotransformation. Concomitant use of fluconazole with nateglinide may prolong its blood glucose–lowering effect51.

4.      Shiling Hu et al has reported that the mode of the action of Nateglinide on KATP current was unique in (a) glucose dependency; (b) increased potency and efficacy under ATP depletion and uncoupling of mitochondrial oxidative phosphorylation than physiological condition; (c) substantially more rapid onset and offset kinetics. The data provide mechanistic rationale for the unique in vivo and ex vivo activity profile of Nateglinide and may contribute to reduced hypoglycemic potential associated with excessive insulin secretion52.

5.      Seham A et al has reported that after the treatment with Nateglinide, a significant reduction was observed in fasting blood glucose levels in all groups. In comparison, nateglinide, when used alone, resulted in a significant increase in cholesterol and total lipid levels. This effect was masked when nateglinide was administered concurrently with metformin and hyperlipidemic effect was noticed53.

6.      Ann Maria K et al has suggested that the ability of the new insulin secretagogues repaglinide and nateglinide to inhibit recombinant human Kir6.2/SUR1 channels was investigated and compared with that of tolbutamide and glibenclamide. Evidence suggests that nateglinide, but not repaglinide, interacts with this region of the channel: binding data, electrophysiological data, and structural considerations54.

7.      Anderson D et al has reported that administration of diclofenac did not alter the pharmacokinetics of nateglinide in healthy subjects. Similarly, concurrent administration of nateglinide with diclofenac did not alter the pharmacokinetics of diclofenac in these subjects55.

8.      Hu s et al has shown that the mechanistic rationale for the unique in vivo and ex vivo activity profile of nateglinide and may contribute to reduced hypoglycemic potential associated with excessive insulin secretion56.

9.      Hansen AM et al has reported that Nateglinide and tolbutamide displaced [(3) H] repaglinide binding to wild-type channels with IC (50) values of 0.7 and 26 micro mol/l, respectively, but produced <10% displacement of [(3) H] repaglinide bound to mutant channels. These results are discussed in terms of a conformational analysis of the drug molecules57.

10.  Sunkara G et al has studied that co-administration of nateglinide does not influence either the pharmacokinetics or the anticoagulant activity of R- and S-acenocoumarol in healthy subjects. This suggests that no dosage adjustments will be required when nateglinide and acenocoumarol are co- administered in clinical practice58.

11.  Scheen AJ et al has reported that Rifampicin (rifampin) reduced repaglinide area under the plasma concentration-time curve (AUC) by 32to85% while it reduced nateglinide AUC by almost 25%. Reported increases in AUCs with co administration of drugs inhibiting CYP isoenzymes never exceeded 80% for repaglinide (except with cyclosporin and with Gemfibrozil) and 50% for nateglinide59.

 

REPAGLINIDE:

 

                  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 secretion60.

 

Structure61:

 

 

Molecular Formula62:

C27H36N2O4

 

Chemical Name61:

 2-ethoxy-4-[2-[[(1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butyl]amino]-2-oxoethyl]benzoic acid

 

Mechanism of Action:

Like the sulphonylureas, repaglinide acts by stimulating release of insulin from the beta-cells of the islets of pancreas inhibiting ATP-sensitive K+ channels, thereby activating the Ca++ channels with increase in intracellular calcium to release insulin63. However, repaglinide acts on a different binding site than the sulphonylureas64,65. Repaglinide is not effective in the absence of functioning beta-cells.

Repaglinide increases the amount of insulin released in a natural and physiological pulsatile pattern66.

The activity of repaglinide is dose-dependent. Mean insulin levels begin to rise approximately 1.5 hours after the preprandial dose of repaglinide and declines towards baseline levels between meal-time67,68.

The rapid onset of action and the short duration of hypoglycaemic effect of repaglinide makes this agent suitable for preprandial administration. The main advantage of preprandial administration is that patients can miss or postpone a meal (and the corresponding repaglinide dose) without increasing the risk of hypoglycaemia or compromising glycaemic control69.

 

Pharmacology of Meglitinides:

Meglitinides lower blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.   Meglitinides interact with the ATP-sensitive potassium (K+ ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped. Adverse reactions include weight gain and hypoglycemia70

 

Pharmacokinetics:

Absorption:

            Rapidly and completely absorbed following oral administration. Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours). The absolute bioavailability is approximately 56%. Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours. When a single 2 mg dose of repaglinide is given to healthy subjects, the area under the curve (AUC) is 18.0 - 18.7 (ng/mL/h)^362.

 

Distribution:

             Repaglinideextensively protein bound (>98%), primarily to albumin62.  The mean absolute bioavailability is 56%.Volume of distribution at steady-state was 31 L following intravenous administration to healthy volunteers71.

 

Metabolism:

            Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide.Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1)72.

Elimination:

            Within 96 hours after dosing with 14C-repaglinide as a single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces72.

 

Interaction of Repaglinide:

By searching through many literatures, it has been revealed that number of researches regarding repaglinide drug interactions had been carried out by so many research scholars as elucidated below.

1.            Mogher Khamaisi et al reported that pre-treatment with Clarithromycin altered the onset of action of Repaglinide, where onset of action, peak effect and duration of antidiabetic effect induced by Repaglinide where significantly severe hypoglycemia73.

2.            Graumlich JF et al suggest that Gatifloxacin and Levofloxacinare kind of protein (serum albumin)that the incidence of hypoglycemic events is greater after treatment with gatifloxacin than levofloxacin. The odds of experiencing hypoglycemic events are greater with gatifloxacin even after adjusting for other hypoglycemia risk factors, such as concomitant hypoglycemic drugs, renal failure, and sepsis syndrome74.

3.            Niemi M et al suggestedthat Gemfibrozil raised by 45% the area under the plasma concentration-time curve (AUC) of repaglinideGemfibrozil alone and in combination with itraconazole considerably potent inhibitors of CYP3A4 with repaglinide may enhance its blood glucose-lowering effect and increase the risk of hypoglycemia; i.e., repaglinide became a long-acting and stronger antidiabetic75.

4.            Vibeke Hatorpet al suggested that repaglinide alone, concomitant ketoconazole increased mean AUC0-∞ for repaglinide by 15% and mean Cmax by 7%. Concomitant rifampicin decreased mean AUC0-∞ for repaglinide by 31% and mean Cmax by 26%76.

5.            Kristian T et al discovered that the concomitant administration of synthetic oral hypoglycemic drugs like Concomitant treatment with CYP3A4 substrates altered mean AUC0–5h and mean Cmax for repaglinide by 1% and 17% (ethinyloestradiol/levonorgestrel)76.

6.            Mikael S et al suggested thatthe incidence of adverse events increased with coadministration of simvastatin or nifedipine compared to either repaglinide or simvastatin/nifedipine treatment alone77.

7.            Mikko Niemiet al found that Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the pharmacokinetics of repaglinide. The effect of SLCO1B1 polymorphism on the pharmacokinetics of repaglinide may be clinically important78.

8.            Carl J Fichtenbaum et al, have reported thatcalcium channel antagonists and Repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4( Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite)79.

9.            Werner et al, suggest that Phenylephrine may interfere with blood glucose control and reduce the effectiveness of repaglinide and other diabetic medications. Monitor your blood sugar levels closely. You may need a dose adjustment of your diabetic medications during and after treatment with phenylephrine. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor80.

10.        Mahmut Bilgic et al, have reported that alpha-lipoic acid may potentiate the hypoglycemic effect of insulin and oral antidiabetic agents. Alpha-lipoic acid has been shown to improve insulin sensitivity and glucose utilization in lean and obese patients with type II diabetes81.

11.        Barbara G et al. reported that Co-administration of pharmacologic dosages of nicotinic acid and adrenocorticotropic agents.These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes82.

12.        Matthieu Roustit et al reported that the Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide83.

 

CANCER:

 

Cancer is the Latin word for crab. The ancients used the word to mean a malignancy, doubtless because of the crab-like tenacity a malignant tumor sometimes seems to show in grasping the tissues it invades. Cancer may also be called malignancy, a malignant tumor, or a neoplasm (literally, a new growth).Benign tumors are NOT cancer; malignant tumors are cancer. Cancer is NOT contagious. An abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).The frequency of a particular cancer may depend on gender. While skin cancer is the most common type of malignancy for both men and women, the second most common type in men is prostate cancer and in women, breast cancer84.

 

There are over 200 types of cancer. such asCarcinoma, Sarcoma, Leukemia, Lymphoma and myeloma, Central nervous system cancers.11Not included in the above types listed are metastatic cancers; this is because metastatic cancer cells usually arise from a cell type listed above and the major difference from the above types is that these cells are now present in a tissue from which the cancer cells did not originally develop. Consequently, if the terms "metastatic cancer" is used, for accuracy, the tissue from which the cancer cells arose should be included. For example, a patient may say they have or are diagnosed with "metastatic cancer" but the more accurate statement is "metastatic (breast, lung, colon, or other type) cancer."85

 

Report reveals that each year more than 12.7 million people undergo cancer diagnosis and over 7 million people die of cancer86.


ABRAXANE:

Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a US National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol. Later it was discovered that endophytic fungi in the bark synthesize paclitaxel.

 

When it was developed commercially by Bristol-Myers Squibb (BMS), the generic name was changed to paclitaxel and the BMS compound is sold under the trademark Taxol. In this formulation, paclitaxel is dissolved in Kolliphor EL and ethanol, as a delivery agent. A newer formulation, in which paclitaxel is bound to albumin is sold under the trademark Abraxane87.

 

Mechanism of Action:

Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine causes the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function87.


Chemical structure of Abraxane:

(2α,4α,5β,7β,10β,13α)-4,10-bis(acetyloxy)-13-{[(2R,3S)- 3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}- 1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate88.

 

Molecular formula:

C47H51NO14.87

 

Pharmacology of Abraxane:

            Abraxane is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis88.

 

Pharmacokinetic:

Metabolism:

In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6αhydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A488.

 

Absorption and Distribution:

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng•h/mL87.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicated that between 89% to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel88.

 

Elimination:

After a 30-minute infusion of 260 mg/m² doses of ABRAXANE, the mean values for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel.

Fecal excretion was approximately 20% of the total dose administered88.

 

DRUG INTERACTIONS OF ABRAXANE:

After through the literature survey, it has been come to know that several researches regarding Abraxane drug interactions study had been carried out by many research scholars as described under.

1.      YAP K et al has reported that clinically significant interaction between Psychotropics are often indicated for these patients since they may also suffer from pre-existing psychological disorders or experience insomnia and anxiety associated with cancer therapy. Thus, the risk of anticancer drug (ACD)-psychotropic drug–drug interactions (DDIs) is high.Pharmacokinetic DDIs were observed for tyrosine kinase inhibitors, corticosteroids and antimicrotubule agents due to their inhibitory or inductive effects on cytochrome P450 isoenzymes. Pharmacodynamic DDIs were identified for thalidomide with central nervous system depressants, procarbazine with antidepressants, myelosuppressive ACDs with clozapine and anthracyclines with QT-prolonging psychotropics. Clinicians should be vigilant when psychotropics are prescribed concurrently with ACDs89.

2.      Beth M Met al has suggested that Recombinant cytochrome P450 (P450) phenotyping, different approaches for estimating fraction metabolized (fm), and multiple measures of in vivo inhibitor exposure were tested for their ability to predict drug interaction magnitude in dogs. In previous reports, midazolam-ketoconazole interaction studies in dogs have been attributed to inhibition of CYP3A pathways90.

3.      Fetell M Ret at has shown paclitaxel given as a 96-hour infusion at the MTD has minimal activity in patients with untreated glioblastoma, the concomitant administration of EIAEDs alters the pharmacology of paclitaxel, resulting in a lower Css, reduced systemic toxicity, and higher dose requirements, this study design, in which a new agent is given prior to radiation therapy (with serial monitoring of MRI), did not adversely affect survival in this patient population91.

4.      Zuylen L V et al has reported that  Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 ( Cremophor EL(CrEL) dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells92. 

5.      Timothy Wet al have evaluated that Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a commonly used chemotherapeutic agent, activated SXR and enhanced P-glycoprotein−mediated drug clearance93.

6.      Stephan Wet al has reported that Rates of death from cardiac causes were 0.6 percent in the sirolimus-stent group and 1.6 percent in the paclitaxel-stent group (P=0.15); the rates of myocardial infarction were 2.8 percent and 3.5 percent, respectively (P=0.49); and the rates of angiographic restenosis were 6.6 percent and 11.7 percent, respectively (P=0.02).As compared with paclitaxel-eluting stents, the use of sirolimus-eluting stents results in fewer major adverse cardiac events, primarily by decreasing the rates of clinical and angiographic restenosis94.

7.      Ahmed Oet al has evaluated that at steady state, Albumin, a versatile protein carrier for drug delivery, has been shown to be nontoxic, non-immunogenic, biocompatible and biodegradable. Therefore, it is ideal material to fabricate nanoparticles for drug delivery. Albumin nanoparticles have gained considerable attention owing to their high binding capacity of various drugs and being well tolerated without any serious side-effects, major outcomes of in vitro and in vivo investigations as well as site-specific drug targeting using various ligands modifying the surface of albumin nanoparticles with special insights to the field of oncology95.

8.      Biren S et al has reported that the In patients with cancer, cumulative results from studies in those with venous thromboembolism (VTE) versus without VTE suggest that anticoagulation therapy, particularly with low-molecular-weight heparins, prevents morbidity and may reduce mortality96.

9.      Howard Aet al has suggested that Concomitant Pazopanib at 200 mg increased paclitaxel maximal concentration (Cmax) by 43% and carboplatin (AUC5 or AUC6) Cmaxby 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of dose-limiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and carboplatin and likely contributed to this effect97.

10.  Robert Fet al has reported that In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel, cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II).Following co administration of Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02)98.

11.  Hesketh PJ et al have reported that Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine99.

12.  Colomer Ret al has reported that Concomitant administration ofpaclitaxel 150 mg/m2 followed by gemcitabine 2500 mg/m2, both on day 1 of 14-day cycles, with a maximum of eight cycles, Forty-three patients received. Serum levels of HER2 ECD were assessed by ELISA.All patients were evaluable for toxicity and 42 for efficacy. Overall toxicity was low. Grade 3 neutropenia occurred in 12% of patients and grade 4 in 17%, and other grade 3 toxicities in <5%. One patient had an allergic infusion reaction. Overall response rate was 71% [95% confidence interval (CI) 62% to 81%], with 11 patients achieving a complete response (26%). With a median follow-up of 26 months, the median time to progression was 16.6 months. Response rate correlated significantly with HER2 ECD, with 42% of HER2 ECD-positive patients responding versus 83% of HER2 ECD-negative patients (P = 0.02). Furthermore, response duration was shorter in patients with positive HER2 ECD levels (7.9 versus 14.4 months; P = 0.04)100.

 

            The literature review is indicating that, there is a possibility of occurrence of drug-drug interaction, when Abraxane and Nateglinide, Abraxane and Repaglinide are concomitantly used. Non-insulin dependent diabetes mellitus is among the most common disorders worldwide, and the number of diabetics, calculated 100 millions, and increases by 6% per year. The incidence of drug-drug interaction ranges from 3-5% in patients taking few drugs and 20% in patients receiving many drugs according to a report that, the drug interaction may be 4th to 6th leading cause for death in United States101.

 

            Therefore the present study was carried out to ascertain the possibility of such interaction.

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