Introduction

Food, dietary supplements and their components can have impact on tlie achievement ol

dmg action and on the side effect profiles of various drugs. Upon entry into the stomach,

food may alter the rate or the extent of drug absorption through a variety of direct and

indirect mechanism. For certain drugs, lx)od may enhance the rate of absorption, while it

may reduce the rate of absolution of other drugs. The interactions are not always

detrimental to therapy, but in some cases can be used to improve dmg absorption or to

minimize adverse effects. These interactions have received more interest recently (Fuhi-,

1998), As new drug approvals occur there is less information available about their

adverse effects, interactions and about the use of herbal medicines and dietary

supplements. These products are not carefully monitored, and may contain little amount

of ingredient mentioned on the label. Some of the herbs used can interact adversely with

prescription drugs such as ephedra and feverfew. Ephedra is a stimulant that can cause

hypertensive crises in patients under monoamine oxidase inhibitors therapy. Feverfew

has anticoagulant properties that can enhance the effects of warfarin (Fleming, 1998;

Lippman and Nash, 1990). Increased acidic environment of stomach results in the

destruction o f acid-labile drugs, such as penicillin G, ampicillin and dicloxacillin

(Beverly et ai, 2003). In other cases, food components such as calcium or iron, may form

complexes with less easily absorbed dmgs like tetracycline, sodium fluoride and

ciprofloxacin (Shah et a/.,l999). In many cases, the actual mechanism by which food

interferes with absorption is not known, but interactions may occur through three

methods: reduced rate or extent of absorption, increased rate or extent o f absorption, or

through chemical/pharmacologic effects (Alonso and Varela, 2000).

The bioavailability of some drugs may be enhanced by food, for example, an acid

environment is necessary for the absorption of ketoconazole. The absorption of

griseofulvin is increased by high fat diet, Fenofibrate, mebendazole, isotretinoin,

tamsulosin, carbamazepirie and labetalol are some examples of drugs that show better

absorption while taken with food (Bennet and Brown, 2003; Sindhu et aL, 2004). There is

a common chemical or pharmacological interaction between alcohol and dmgs that have

sedative effects like opiates, benzodiazepines and antihistamines.The effect o f these

dmgs are usually potentiated by the consumption o f alcohol. Another alcohol-related

Chapter I _____________________________________________ Introduction

Ph. D Thesis 1 " Jam iaHamdard

interaction is tlie competitive inhibition o f the enzyme aldehyde dehydrogenase. Nausea,

vomiting, flushing, dizziness and tachycardia may occur with exposure to alcohol in

patients taking some cephalosporins, ketoconazole, metronidazole and sulfonylureas. In

addition, chronic alcohol overuse can increase the toxicity o f some drugs, as with

acetaminophen and methotrexate, or reduce the drugs efficacy, as with phenytoin (Lieber,

1994).

Components o f food may antagonize the desired effect o f the drug, as in the case o f

warfarin. Vitamin K containing foods reduce the effectiveness of warfarin. Changing to a

diet with increased consumption of leafy and/or dark green vegetables, such as spinach

and turnip greens, could decrease the degree of anticoagulation effect of warfarin due to

additional supply of vitamin K (Booth et ai, 1997). Perhaps the most feared food-drug

interaction is that between monoamine oxidase inhibitors (MAOIs) and tyi'amine, which

is found in a variety of aged, fermented, overripe or pickled foods and beverages and, to a

lesser extent, chocolate and yeast-containing foods. Tyramine is indirectly

sympathomimetic, when its metabolism is suppressed as by MAOIs, it can cause a

significant release o f norepinephrine, resulting in markedly increased blood pressure,

cardiac arrhythmias, hyperthermia and cerebral hemorrhage (Brown et al, 1989;

Livingston and Livingston, 1996). There are variety o f dmgs that show interaction with

flavonoids found in grapefruit juice that leads the inhibition of certain enzymes in the

cytochrome P450 system, which results in reduced metabolism of drugs that are cleared

by the same system (Bailey et al., 1998). Some examples of food and its components

affecting dmg absorption, disposition and their efl^ct as given as under:

(1) Antibiotics

® Cephalosporins, penicillin: Acid secreted by gut after food destroy these acid

labile daigs.

® Erythrom ycin: Fruit juice or wine consuption decrease the drug's effectiveness.

® Tetracycline: Dairy products reduce the drug's absorption and effectiveness.

(2) Anticonvulsants

® Dilantin, phenobarbital: Increase the risk of anemia and nerve problems due to

deficiency of folalte and other B vitamins.

chapter 1 ___________________________ Introduction

Ph. D Thesis 2 Jamia Hamdard

(3) Antidepressaiits

LithiMiii: A low-salt diet increases the risk o f lithium toxicity; excessive salt

reduces the drug's efficacy.

MAO inhibitorss Foods high in tyramine (aged cheese, processed meaits,

legumes, wine and beer among others) can produce a hyfiertensive crisis.

® Tricyclics: Many foods, especially legumes, meat, fish and foods high in Vitamin

C reduce absorption of the drugs,

(4) Antihypertensives and heart medications

® ACE inhibitors: Food lowers the absorption of the drugs.

® Alpha blockers: Liquid or food avoid excessive drop in blood pressure.

» A ntiarrhytlim ic drugs; Caffeine increases the risk of irregular heartbeat.

® Beta blockers; Food, especially meat, increases the drug's effects and can cause

dizziness and low blood pressure.

® Digitalis: Milk and high liber foods, which reduce absoiption, increases

potassium loss.

(5) Asthma drugs

® Pseudoephedrine: Caffeine increase feeling of anxiety and nervousness.

® Theophylline: High protein diet reduces absorption. Caffeine increases the risk o f

drug toxicity.

(6) Cholesterol lowering drugs

® Cholestyramine: Increases the excretion of folate and fat soluble vitamins.

® Gemfibrozil; Fatty foods decrease the drug's efficacy in lowering cholesterol,

(7) H eartburn and ulcer medications

“ Antacids: Interfere with the absorption of many minerals.

® CImetidine, famotidine, sucralfate: High protein foods, caffeine and other items

that increase stomach acidity.

(8) Hormone preparations

® O ral contraceptives: Salty foods increase fluid retention. Dmgs reduce the

absorption of folate, vitamin B6 and other nutrients.

® Thyroid drugs; Iodine-rich foods lower the dmg's efficacy.

Chapter I__________ ____________________________________________ Introduction

Ph. D Thesis 3 Jamia Hamdard

(9) Laxatives

‘s IVIiiiera! Oils; Overuse can cause a deficiency o f vitamins A, D, E, and K,

(10) Painkillers

a Aspirin and stronger nonsteroiclfi! asiti-iiiflamrnatory drugs: Food lowers the

risk of gastrointestinal irritation. Alcohol increases the risk o f bleeding.

(11) SleepiMg pills, tranquilizers

® Benzodiazepines; Caffeine increases an.x.iety and reduce drug's ettectiveness

(Sarah, 1998; Williams et al.. 1996; Anonymous, 2003; Walker e( al.. 1996).

According to the Code of Federal Regulations, bioavailability is the rate and extent

(fraction or the percentage of the dose) to which the active drug ingredient or therapeutic

moiety is absorbed from a dtxig product and becomes available at the site of drug action

(Lobenberg and Amidon, 2000). Oral bioavailability depends on a number of factors,

primarily drug penneabllity, aqueous solubility, dissolution rate, presystemic metabolism,

first-pass metabolism and susceptibility to efflux mechanisms. Among these l^ictors low

permeability and poor solubility stands as the most frequent causes o f low oral

bioavailability (Burnside et al., 2005).

Food and its components interact with co-adrninistered drugs and affect their availability

across intestine. Several pharmacokinetic parameters are used to judge the clinical

importance of fbod/dmg interachons. The concept that botanical supplements could

interact with conventional medications is understandable given that food-drug

interactions have been recognized ftir a variety of fruits, spices and vegetables that

constitute part of the nonnal human diet. Many food-drug interactions have

phytochemical-mediated pharmacokinetic components. For example, iuranocoumarins

present in grapefruit juice inhibit intestinal CYP3 A4 and have been shown to increase the

oral bioavailability of medications that are CYP3A4 substrates e.g., felodipine,

midazolam, cyclosporine. The human diet contains many different nutrients, several

compounds that are not nutrients, and additives. According to studies where effects of

carbohydrates, fat and proteins (macro-nutrients) were determined on drug absorption

and metabolism, changes in micro- and macro-nutrient composition of the diet can affect

absoiption and/or elimination of drugs (Welling, 1996). The effects of non-nutrients and

Chapter 1 _____________ ___________________________________

Ph. D Thesis 4 Jamia Hamdard

additives in food may also exert an et'fect on bioavailability of dmgs. Some drugs, which

normally are not interacting with food components, might interact during absoiption with

the components of plant material, causing unexpected drug effects, such as several times

higher or lower dmg concentrations in the circulation (Wallace and Amsden 2002).

Polyphenols (e.g. anthocyanins, couniarins, flavonoids, lignans and tannins), present in

herbs, vegetables, fmits, flowers, and leaves in many plants, are believed to be beneficial

to human health by exerting biological effects such as free radical scavenging.

Bioavailability of polyphenols has been studied in~vivo (Hollman et al., 1995; Miyazawa,

2000) and in-vitro (Kuo et a l, 1998, Murota et al., 2000, 2002). Most dietary flavonoids

present in food exist as 0-glycosides with glucose, glucorhamnose, galactose, arabinose,

or rhamnose (Heim et al., 2002). The f3-linkage of these glycosides resist hydrolysis

caused by acidity in the stomach and the attack by pancreatic enzymes, However, (3-

endoglucosidases present in small intestine are able to hydrolyse flavonoid glycosides

(Spencer et al., 1999). Additionally, colonic microflora hydrolyses the sugar moiety from

the flavonoid aglycone, thus increasing the absorption of flavonoids, During absorption,

the flavonoids may interact with metabolising enzymes and transport proteins, and thus

affect the uptake of co-administered drugs. Indeed, polyphenols are potent inhibitors or

inducers of CYPs, UGTs and transport proteins, if consumed in large amounts (Zhai et

al., 1998, Conseil et al,, 1998, Ohnishi cl al., 2000). Spices along with their components

may also effect drug absorption and metabolism.

Some natural compounds have demonstrated to increase the absorption and

bioavailability of co-administered drugs. Bioavailability and absoiption enhancement

through co-administration of drugs with natural compounds from plants are considered to

be very simple and comparatively safe. Bioavailability enhancing activity of natural

compounds from medicinal plants may mainly be attributed to various mechanisms such

as P-gp inhibition activity, non-specific mechanisms promoting rapid absorption o f drugs

such as increased blood supply to the gastrointestinal tract, decreased hydrochloric acid

secretion preventing breakdown of some drugs, non-specific mechanisms inhibiting

enzymes participating in metabolism of drugs. In many cases, bioavailability and

absorption-enhancing effect of natural compounds from medicinal plants were reported to

be attributed to inhibition of P-gp, Flavone, quercetin and genistein have showed a

Chapter I _______________________________________ Introduction

Ph. D Thesis 5 Jamia Hamdard

Chapter I Introduction

considerable P-gp inhibition activities. Additionally, naringin and sinomenine were also

reported to be inhibitors for efflux transporters such as P-gp and breast cancer resistance

protein (Tsai et a l, 2001; Chan et al., 2006). Attenuation of physical barrier such as an

increase in intestinal brush border membrane fluidity and inhibition o f metabolic

enzymes participating in biotransformation of drugs were reported to be absorption

enhancing mechanisms of natural compounds (Khajuria et al., 2002). Many absorption

enhancers are effective in improving the intestinal absorption, such as bile salts,

surfactants, fatty acids, chelating agents, salicylates and polymers as shown in Table 1.1

(Lundin et a l, 1990; Aungst et a l, 1991). Surfactants including bile, bile salts and fatty

acids act as absoiption enhancers by increasing the solubility of hydrophobic drugs in the

aqueous layer or by increasing the fluidity of the apical and basolateral membranes.

Calcium chelators such as EDTA i-educe the extracellular calcium concentration, leading

to the dismption of cell-cell contacts. Chitosan, particularly trimethylated chitosan, was

reported to increase dmg absorption via paracellular route by redistribution o f the

cytoskeletal F-actin, causing the opening of the tight junctions (Schipper et al., 1997).

Table 1.1 List of compounds shown to have intestinal absorption eiiliaiidiig effects

Category Compounds

Bile salts Sodium cholate, sodium deoxycholate

NoEi“ioEic surfactants Polyoxyethylene alkyl ethers, polysorbates

Ionic surfactants Sodium lauryl sulfate.

Dioctyl sodium sulfosuccinate

Fatty adds Sodium caprate, oleic acid, glycerides, natural oils,

medium-chain glycerides, phospholipids,

polyoxyethylene glyceryl esters,

acyl carnitines and cholines,

palmitoyl carnitine, lauroyl choline

Salicylates Sodium salicylate, sodium methoxysalicylate

Chelating agents EGTA, EDTA

Swellable polymers Starch, polycarbophil, chitosan

Others Citric acid

Ph. D Thesis ^ Jarnia Hamclard

Phytocoiistitueiits as bioenharicers

Quercetln

Quercetin is a flavonoid found in citrus I'ruits, It is reported that this flavanoid increase

bioavailabihty, blood levels and efficacy of a number o f drugs such as diltiazem (Choi

and Li, 2005), digoxin (Wang et a!., 2004) and epigallocatechin gallate (Anup et a/.,

2005), The absorption of epigallocatechin gallate has been enhanced with red onion

supplementation, which is a rich source of quercetin. The AUC of epigallocatechin

gallate determined over a period of 6 h increased from 1323 to 1814 ng.h/ml, when co­

administered with quercetin.

Genlstetn

Genistein, well known as a phytoestrogen (Kurzer and Xu, 2003) inhibits P-gp, BCRP

and MRP2 efflux function. The intestinal absorption of paclitaxel, a substrate for efflux

transports such as P~gp, BCRP and MRP2 considerably increased when co-administered

with genistein. It has been reported that the inhibition of the efflux transporters by

genistein improve systemic exposure of paclitaxel (Li and Choi, 2007),

Nariiigin

Naringin is the major flavonoid glycoside found in grapefruits, that shows the inhibition

of P“gp and CYP3A in rats (Zhang el a!., 2000). AUC of paclitaxel is increased

significantly in presence of naringin (49,1% for naringin at 10 mg/kg) (Lim and Choi,

2006).

Sinomenine

Paeoniflorin, bioactive monoterpene glucoside has a poor bioavailability (3-4%) when

administered orally (Takeda et aL, 1995). Co-administration o f paeoniflorin with

sinomenine, an alkaloid extracted from Sinomenium acutim, significantly altered the

pharmacokinetic behaviors of paeoniflorin in rats (Liu et ciL, 2005). The results of AUC

obtained in the study demonstrated that oral bioavailability of paeoniflorin was enhanced

by more than 12 times in rats treated with sinomenine.

Piperine

Piperine is a major alkaloidal component of Piper nigrum Linn. Piperine, or mixtures

containing piperine, has been shown to increase the bioavailability, blood levels and

efficacy of a number of drugs including vasicine, sparteine, sulfadiazine, rifampicin,

Chapter I_______________________________________________ ___________

Ph, D Thesis 7 Jamia Hamdard

phenytoin and propranolol (Atal el al„ 1981; Bano et al„ 1987; 1991).

Glycyrrliizin

Glycyrrhizin is a, triterpenoid saponin Ibund in Glycyrrhiza glabra Linn, Glycyrrliizin

showed a more potent absorption enhancing activity than caproic acid at the same

concentration tested (Liiai et al., 2005). The absorption-enhancing activity of sodium

deoxycholate and dipotassium-glycyrrhizinate was much greater when coadministered

with glycyrrhizin. The absoiption enhancing activity of glycyrrhizin was increased by

presence of other absoiption enhancers (Sakai et al., 1999; Imai et al., 2005).

Nitrile glycosides

Nitrile glycosides and its derivatives are components derived from the pods of Moringa

oleifera Lam. These glycosides enhanced the absorption of commonly used antibiotics

such as rifampicin, tetracycline and ampicillin, vitamins and nutrients (Khanuja et al.,

2005).

CiMtiin oil

Cuminum cyminum Linn, is an annual herb, its fruits are generally used as spice.

Bioavailability enhancing activity of C. cyminum was revealed toward a number o f drugs

(Qazi et al., 2009). Various volatile oils and luteolin and other flavonoids seemed to

attribute the bioavailability/bioefficacy enhancing activity. Especially luteolin has

demonstrated to be a potent P-gp inhibitor in the literature (Boumendjel et a l, 2002).

Pepperinliit oil

Peppermint oil extracted from mentha species increased cyclosporine maximum

concentration (C„,aO and area under the concentration versus time curve (AUCo-a) from

0.60 to 1.6 fig/ml and 8.3 to 24.3 ng.h/ml respectively (Wacher et a/.,2002).

Chapter I _____________________________________________________ Introduction

Ph. D Thesis 8 Jamia Hamdard

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Chapter I_____ ___________________________________ ____ ____________ Introductim_

Ph. D Thesis 12 Jarnia Hamdard

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