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;
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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