WO2007133476A2

WO2007133476A2 - Competitive substrate inhibition to increase drug bioavailability

Info

Publication number: WO2007133476A2
Application number: PCT/US2007/010806
Authority: WO
Inventors: Eric Holmes
Original assignee: Scolr Pharma, Inc.
Priority date: 2006-05-08
Filing date: 2007-05-04
Publication date: 2007-11-22
Also published as: TW200808353A; WO2007133476A3

Abstract

The present invention is directed to a method and a composition for improving the bioavailability of an orally administered drug having poor systemic bioavailability, by competitively inhibiting and retarding the metabolic inactivation of the drug.

Description

COMPETITIVE SUBSTRATE INHIBITION TO INCREASE DRUG BIOAVAILABILITY

FIELD OFTHE INVENTION

The present invention is directed to a method for improving drug bioavailability by competitively inhibiting and retarding the metabolic inactivation of drugs having poor systemic bioavailability.

BACKGROUND OF THE INVENTION

Drug bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route. (B. Katzung, Basic & Clinical Pharmacology, Norwa Ik CT: Appleton & Lange 1995, page 39). Poor drug bioavailability can result from low drug solubility, low drug permeability, and any metabolism of the drug.

In order to reach its site of action in the body, a drug must first be absorbed into the blood from its site of administration. Orally administered drugs are generally absorbed into the blood from the gastrointestinal (GI) tract and must pass through the cell membranes of GI tract cells and blood vessel cells to enter the blood stream. The inherent ability of a compound to pass through a barrier such as a cell membrane, is known as permeability. J. B. Dressman & H. Lennernas, Oral Drug Absorption: Prediction and Assessment, Drugs and the Pharmaceutical Sciences 106, Marcel Decker, New York, 2000, pages 11-16.

Cell membranes are made up of a lipid bilayer, and the physicochemical properties of a drug compound determines how easily the compound can permeate the cell membranes and be absorbed from the GI tract into the circulation. Lipid-soluble compounds (lipophilic compounds) will easily permeate the lipid bilayer and are highly permeable to intestinal epithelial cell membranes. However, lipophilic compounds generally exhibit poor water solubility and may be rapidly metabolized, which decreases bioavailability. For example, the lipophilic drug, raloxifene hydrochloride (raloxifene- HCI), is readily absorbed through the intestinal wall following oral administration, but due to intense pre-systemic metabolism, the bioavailability of raloxifene Is only 2%. EJ Jeong, et a/. (2005), Drug Metab Dispos. 33, 785-794.

Metabolism of lipophilic compounds generally involves reactions leading to more hydrophilic structures that are readily eliminated. One such reaction, glucuronidation, involves the transfer of glucuronic acid from UDP-glucuronic acid to substrate compounds to form glucuronidated compounds. Glucuronidation is catalyzed by two families of UDP- glucuronosyltransferases (UGT's), UGTl and UGT2, each of which is expressed on the luminal side of the endoplasmic reticulum and each of which has multiple splice variants, differing tissue distributions, and differing substrate specificities.

Although the liver is considered the major organ for drug metabolism (including glucuronidation reactions catalyzed by a variety of isozymes, for example, UGTlAl, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15), intestinal and colonic epithelial cells also play a role in the metabolism of lipophilic drug compounds. P.A. Gregory, et al. (2004), Toxicol. Appl. Pharmacol. 199, 354-363; CP. Strassburg, et al., (1998) J. Biol. Chem 273, 8719-8726. UGT1A8 and UGTlAlO, which share approximately 94% amino acid sequence homology, are UGT isoenzymes that are expressed in human, intestinal and colonic epithelia, but not in liver cells. Z. Cheng, et al. (1999), Drug Metab. Disp. 27, 1165-1170; Strassburg, et al., (1998) J. Biol. Chem 273, 8719-8726. Glucuronidation by these enzymes in intestinal epithelia plays a major role in the metabolism and elimination of certain lipophilic drug compounds, and, accordingly in the bioavailability of these drugs. It has now been found that the amount of presystemic metabolism of a drug can be reduced by concurrent or subsequent oral administration with the drug of a competitive inhibitor as a substrate for these enzymes. As a result, the bioavailability of the drug is increased.

SUMMARY OF THE INVENTION The present invention comprises a method and composition for improving the bioavailability of a drug that is metabolized by one or more metabolizing enzymes in the intestinal epithelium or in the liver. The invention comprises orally administering to a patient in need thereof a therapeutic amount of the drug in combination with a suitable competitive inhibitor, the competitive inhibitor being administered in an amount sufficient to effectively compete with the drug for at least one metabolizing enzyme.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph of the mean plasma raloxifene-HCI concentration versus time for treatment groups A (49.5 mg raloxifene-HCI) and C (49.5 mg raloxifene-HCI + 2 Citrus Bioflavonoid Capsules). DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to increasing the bioavailability of a drug that is subject to presystemic metabolism by orally administering one or more suitable competitive substrate inhibitors for one or more enzymes that metabolize the drug in the ϊntestinal/colonic epithelium, the liver, or both. A suitable competitive inhibitor is a compound that is either pharmacologically inactive or has weak pharmacological activity, and competes with the drug for the metabolic enzymes that lead to the degradation and elimination of the drug. Suitable competitive inhibitors, whether physiologically active or inactive, are those which are compatible with the drug in question; do not present any adverse drug interaction, either chemically of physiologically, and do not cause any significant side effects due to interaction between the drug and competitive inhibitor.

The competitive inhibitors act as substrates that compete effectively with the drug for the enzyme that effects presystemic metabolism of the drug. A competitive inhibitor "effectively competes" with a drug when it causes a detectable reduction in the amount of a given metabolic reaction of the drug that would otherwise occur in the absence of the competitive inhibitor.

Competitive inhibitor compounds may have weak or no pharmacological activity, and may have some physiological function. Administration of the competitive inhibitor with the drug will result in reduced metabolism of the drug in intestinal or colonic epithelium or liver, thereby enhancing the drug's systemic bioavailability. When systemic bioavailability is increased (AUC and/or Cmax), less drug can be administered, and inter-subject variability in plasma drug levels due to genetic polymorphisms in metabolic enzymes is diminished.

In one embodiment of the invention, the competitive inhibitor effectively competes with the drug as a substrate for metabolizing enzymes comprising UDP- glucuronosyltransferases (UGT) as a substrate for UGT glucuronidation. One type of UGT substrate capable of acting as an effective and suitable competitive inhibitor of drug glucuronidation is a bioflavonoid. Bioflavonoids are a group of compounds produced in plants that are structurally based on phenylbenzopyrone. They occur in several forms, including hesperidin, eriodictyl, quercetin, rutin, hesperitϊn, 7-hydroxyflavone, chrysin, apigenin, fisetin, naringenin, and genistein. Bioflavonoids are generally considered to be dietary components or supplements that may also provide some natural antiviral, antiinflammatory, anti-allergenic, and antioxidant properties. M. Hu, et al., (2003), J. Pharmacol. Exp. Ther, 307, 314-321, and references cited therein. Bioflavonoids are substrates for UGTs, and bioflavonoid components are known to be highly glucuronidated by human UGT enzymes expressed in the liver and in intestinal and colonic epithelia, including the UGT1A8 and UGTlAlO intestinal isozymes. Z. Cheng, et at., (1999), Drug Metab. Dispos. 27, 1165-1170; CP. Strassburg, et a/., (1998) J. Biol. Chem. 273, 8719- 8726; D.C. Kemp, et al., (2002), Drug Metab. Dispos. 30, 694-700; M.G. Boersma, et al., (2002), Chem. Res. Toxicol. 15, 662-670; R.H. Lewinsky, et at., (2005), Xeπobiotica 35, 117-129. Therefore, in one embodiment of the invention, the competitive inhibitor is a bioflavonoid. Other UGT substrates that are suitable competitive inhibitors include aspirin, acetominophen, ibuprofen, naproxen, ketoprofen, anthraquinones such as anthraflavic acid, alizarin, or emodin, fatty acids, retinoids, phenolic compounds such as eugenol or mycophenolic acid, and coumarins such as scopoletin. (N. K. Basu, et ah, (2004) J. Biol. Chem. 279, 28320-28329, corrections at p. 54972; K. Bowalgaha et al., (2005) Br. J. Clin. Pharmacol. 60, 423-433; Z. Cheng, et a/., (1999), Drug Metab. Dispos. 27, 1165- 1170; G. E. Kuehl, et al., (2002) Drug Metab. And Disp. 34, 199-202; LJ. Webb, et a/., (2005) Drug Metab. Dispos. 33, 77-82).

The criteria for selecting a suitable competitive inhibitor depends primarily on the substrate specificity of the UGT isozyme, the reaction kinetics of the competitive inhibitor, and the extent of possible adverse pharmacological activity of the competitive inhibitor. Assays for determining enzyme substrate specificity and kinetics for a particular substrate are known in the art. For example, assays for UGT enzymes have been described by Z. Cheng, et al._r (1999), Drug Metab. Dispos. 27, 1165-1170; and Webb, et al., (2005) Drug Metab. Dispos. 33, 77-82.

Drugs whose bioavailability may be improved through co-administration with a competitive inhibitor are those that are highly lipophilic and/or have limited bioavailability due to presystemic metabolism. These include, but are not limited to, raloxifene, fenofibrate, gemfibrozil, arzoxifene, troglitazone, sertraline, olanzapine, celecoxib, venlafaxine HCI, rosiglitazone, pioglitazone HCI, ondansetron, topiramate, lamotrigine, ramϊpril, carvedilol, ezetimibe, atomoxetine, desloratadine, mycophenolate mofetil, oxcarbazepine, tegaserod, bicalutamide, moxifloxacin, divalproex, and furosemide.

Presystemic drug metabolism, also referred to as first-pass metabolism, denotes metabolic reactions that occur in tissues early in the absorptive phase of a drug, prior to the release of a drug into the systemic blood circulation. This can also be referred to as first-pass metabolism which is catalyzed by a variety of enzymes including UGTs and cytochrome P450 (CYP) activities. Presystemic metabolism takes place primarily in the liver, but also occurs in intestinal, colonic and in respiratory epithelia. P.A. Gregory, et al. (2004), Toxicol. Appl. Pharmacol. 199, 354-363; CP. Strassburg, et al., (1998) J. Biol. Chem 273, 8719-8726. Because the enzymes that effect presystemic metabolism demonstrate substrate specificity and tissue-specific distribution, it is possible to improve drug bioavailability by reducing the extent of presystemic metabolism in the intestine or the liver using suitable competitive inhibitors. In one embodiment, this invention takes advantage of the substrate specificity and tissue distribution of UGT isozymes to inhibit presystemic metabolism of a drug via glucuronidation. Isozymes, or isoenzymes, are chemically distinct forms of an enzyme that perform the same biochemical function. By adding a compound that competes with the drug as a substrate for a particular UGT isozyme, presystemic metabolism of the drug is diminished and systemic bioavailability of the drug is increased. For example, raloxifene is a drug used in the treatment of osteoporosis.

Approximately 60% of the usual dose of raloxifene is absorbed in the gastrointestinal tract, yet it has been shown to have only a 2% systemic bioavailability in humans. EJ Jeong, et al. (2005), Drug Metab Dispo. ,33, 785-794. Raloxifene is a substrate for UGT1A8 and UGTlAlO enzymes. Glucuronidation in intestinal epithelial cells by UGTlAlO, which leads to the rapid elimination of raloxifene, is thought to be primarily responsible for raloxifene's low systemic bioavailability. EJ Jeong, et a/. (2005), Drug Metab Dispos. 33, 785-794. By comparison, in rats, which lack the UGTlAlO enzyme, the systemic bioavailability of raloxifene is 39%. EJ Jeong, et a (2005), Drug Metab Dispos. 33, 785-794. Thus, reducing the metabolism of raloxifene in the intestinal epithelium should result in substantially increased systemic bioavailability of the drug. This is shown below in Example 1.

Raloxifene, fenofibrate, arzoxifene, and troglitazone, and compounds structurally related to raloxifene have been shown to be substrates for glucuronidation by UGT1A8 and/or UGTlAlO. EJ Jeong, et al. (2005), Drug Metab Dispos. 33, 785-794; A. Weil, et al., (1988) Drug Metab. Dispos. 16, 302-309; K.C. Morello, et al., (2003) Clin.

Pharmacokinet. 4,;361-72; Y. Watanabe, et al., (2002) Drug Metab. Dispos. 30, 1462- 1469.

Furthermore, compounds which are substrates for UGT1A8 and/or UGTlAlO have structural features in common that are required for UGT1A8 and/or UGTlAlO specificity. These features include a high degree of planarity, the presence of multiple rather than single aromatic ring systems, and ring substituents that lie in the plane of the ring system. Webb, et al., (2005) Drug Metab. Dispos. 33, 77-82. Drugs bearing these specific structural features are likely to be specific substrates for UGT1A8 and/or UGTlAlO. In addition, assays have been described that can be used to determine whether a particular drug is a UGT1A8 and/or UGTlAlO substrate. Z. Cheng, et al., (1999), Drug Metab. Dispos. 27, 1165-1170; and Webb, et a/., (2005) Drug Metab. Dispos. 33, 77-82. Bioflavonoids and other suitable competitive inhibitors may be administered to increase the systemic bioavailability of such drugs.

The process for matching a drug and a competitive inhibitor, and selecting appropriate ratios of drug and competitive inhibitor for oral adminstration relies on processes that are well known to one of ordinary skill in the arts of enzymology and pharmacology. Standard pharmacokinetic studies of drug compounds can be used to determine what metabolites of a particular drug are formed in vivo, the excretion route and rate for that drug, and the resulting bioavailability of the drug, by quantifying a variety of standard parameters (e.g. AUC, Cmax, tχ_/2/ etc.). These methods are well known in the art. See, for example, D. A. Smith, et al., Pharmacokinetics and Metabolism in Drug Design, in Methods and Principles in Medicinal Chemistry, Vol. 31, R. Mannhold, H. Kubinyi, and G. Folkers, Eds., Wiley-VCH: New York 2006, and references therein; and R.D. Schoenwald, Ed. Pharmacokinetics in Drug Discovery and Development , CRC Press: Boca Raton 2002, and references therein. This information, including metabolite structures and concentrations, can then be used to determine whether or not a particular drug is subject to presystemic metabolism, such as glucuronidation.

UGT enzymes obey Michaelis-Menton kinetics. As a result, the K_m value for the drug and competitive inhibitor for a given UGT can be determined through simple UGT assays. The K_m is the substrate concentration of the drug that is required for the enzyme to be at Vi V_maχ- V_m3x is the maximum initial velocity of an enzyme catalyzed reaction at saturating substrate levels. Enzyme saturation curves can be generated using a series of reaction mixtures containing increasing drug concentrations in both the absence and presence of multiple fixed concentrations of the competitive inhibitor acting as an alternate substrate. The resulting data yields a series of saturation curves at differing competitive inhibitor concentrations and can be plotted using a variety of standard equations to yield a K| for the competitive inhibitor with respect to drug glucuronidation. The Kj is given in units of concentration and for a competitive inhibitor is essentially the competitive inhibitor concentration which reduces the enzyme V_maχ for the drug substrate by half. These data are used to select the desired ratio of the competitive inhibitor to the drug for use in an oral formulation. In general, for each multiple of Ki (also referred to as fold-KO over the multiple of K_m (fold-K_m) concentration, the level of inhibition would follow the following relationship: a 1: 1 competitive inhibitor to drug ratio (competitive inhibitor fold-Kι:drug fold-K_m) would reduce drug glucuronidation by 1/2, a 2: 1 ratio would reduce it by 2/3, a 3: 1 ratio would reduce it by 3/4, and so on. This follows the general equation (Equation 1) of: Drug Metabolism

Inhibition= [inhibitor amount present in terms of fold-K|]/[drug amount present in terms of fold-K_m]+ [inhibitor amount present in terms of fold-K|]. Because K₁ and K_m kinetic constants are in units of concentration (e.g., moles per liter) and for the intended purpose herein would be used in the same solution, the volume parameters for K₁ and K_m are the same. It is anticipated that the useful drug to competitive inhibitor ratio in terms of competitive inhibitor fold-Kiidrug fold-K_m may be within the range of about 0.01 to 50. This ratio will depend, in part, on the relative affinity of the enzyme for the drug and the competitive inhibitor. These affinities are easily determined by methods well known in the art.

Subsequent to these pharmacokinetic studies, in vitro enzyme assays, such as those described by Z. Cheng, et al. (1999), Drug Metab. Disp. 27, 1165-1170; Strassburg, et a/., (1998) J. Biol. Chem 273, 8719-8726 and LJ. Webb, et a/., (2005) Drug Metab. Dispos. 33, 77-82, can be performed to analyze the kinetics and substrate specificity of UGTs for the drug, and to determine the major tissue site of glucuronidation. For these assays, UGTs are obtained from either liver or intestinal epithelial microsomal preparations. Recombinant UGT enzymes may also be used. Because the tissue distribution (e.g., liver or intestinal epithelia) of specific UGT isozymes is known, these assays will determine whether a given drug is glucuronidated in the intestinal epithelium, the liver, or both. These assays can also be used to examine pharmacologically inactive or weakly active competitive inhibitors to determine which UGT isozymes metabolize them and the kinetic parameters of the UGT-competitive inhibitor interaction.

Depending on the extent of presystemic glucuronidation of a specific drug, the effective drug concentration, competitive inhibitor requirements, final dosage form size, and the site of major glucuronidation activity, a test formulation can be prepared for in vivo clinical assessment. Clinical studies would be designed to quantify the effects of competitive inhibitor content on drug pharmacokinetic parameters and determine the amount of competitive inhibitor necessary to effectively compete with the drug as a substrate for the metabolizing enzymes. The amount of competitive inhibitor that effectively competes with a particular drug as a substrate for a metabolizing enzyme is defined as an amount of competitive inhibitor that produces a detectable increase in the bioavailability of the drug. Based upon these results, alterations can then be made to adjust drug bioavailability and/or metabolism as needed through changes in drug and/or competitive inhibitor concentration.

Using the methods described, the fold-Ki:fold-K_m ratio of competitive inhibitor to drug can be varied to achieve a desired drug bioavailability. A higher ratio provides more protection for the drug from glucuronidation compared to a lower ratio. Thus, it would be possible to achieve a target systemic bioavailability (as expressed in terms of AUC and/or Cmax) by adjusting the relative levels of competitive inhibitor and drug. The desired competitive inhibitor to drug ratio is a function of the properties of a specific drug and the specific competitive inhibitor used. This is because a given enzyme can have binding specificity, but widely varying affinities (in terms of values for K_m and Ki kinetic constants), for multiple substrates and inhibitors. Thus, a ratio of fold-Ki:fold-K_m corrects for affinity differences and allows more direct comparison and evaluation. This ratio can be readily determined through in vitro assays and can be used in monitoring drug bioavailability in animal or human subjects. The bioavailability of a given drug concentration at varying competitive inhibitor levels (or fixed levels of competitive inhibitor and varying drug amounts) can be used to develop optimal dosages for the drug and the competitive inhibitor. Taking these factors into consideration, a suitable dosage may comprise a competitive inhibitor fold-Kjidrug fold-K_m ratio within the range of about 0.01 to about 50, for example, about 0.02 to about 10, more particularly about 0.05 to about 5.

Different embodiments of the invention are directed to drug/competitive inhibitor combinations that reduce presystemic glucuronidation of the drug specifically in liver, in the intestinal and/or colonic epithelium, or in both liver and intestinal (and/or colonic) epithelium. For example, the drug/competitive inhibitor combination may be directed to reducing presystemic glucuronidation catalyzed specifically by UGT1A8 and UGTlAlO which are expressed in intestinal and colonic epithelia, but not in the liver. For purposes of administration, drug compounds can be mixed with one or more competitive inhibitor and other pharmaceutically acceptable excipients for oral delivery using methods well known in the art of formulation science. It will be appreciated that the drug and competitive inhibitor may be formulated and administered orally as a tablet, capsule or other unit dosage form, or at the same time as separate dosage forms. In formulating the combined ingredients into tablets, capsules or other solid dosage forms, there may be included various formulation excipients including lubricants, flow aids, flavorings, taste masking ingredients, compression aids, etc., all of which are well known to those skilled in the art.

It will also be apparent that the compositions may also be formulated as syrups, suspensions, or other liquid forms, as well as powders or tablets for oral ingestion, also with excipients generally used for such dosage forms. Likewise the drug and competitive inhibitor may be administered in a single liquid or as two separate liquids administered at the same time.

The following non-limiting examples are described to provide direction in the use of this invention.

EXAMPLE 1. Clinical Effect of Mixed Bioflavonoids on Raloxifene Bioavailability

Clinical trials were conducted by Biovail Contract Research (Study No. 3278) to determine the effects of mixed bioflavonoids on raloxifene bioavailability. The subjects were 36 post-menopausal women who were randomly placed into four treatment groups. Data for two groups, reflect formulations A and C, are reported below. The bioflavonoid administered was TwinLab Citrus Bioflavonoid gelgaps, which contain 700mg of mixed bioflavonoids including flavanones (hesperidin, eriocitrin, naringen, naringenin), flavonols, flavones, and lOOmg of rutin. Raloxifene tablets and Citrus Bioflavonoid gelcaps were administered orally.

Following an overnight fast (1Oh minimum), subjects receive one of the following treatments:

A Raloxifene-HCI 49.5 mg tablet

B Raloxifene-HCL 60 mg tablet

C Raloxifene-HCI 49.5 mg tablet followed by 2 Citrus Bioflavonoid gelcaps

Dosage C is estimated to have a fold-Kj:fold-K_m ratio of approximately 0.5. This is based upon known K_m values of raloxifene and an estimated average Ki value for the component bioflavonoids present in the capsules used. The Kj values for the component bioflavonoids have not all been determined. The estimated Kj for the mixture is based upon published kinetic studies involving bioflavonoid components (Z. Cheng, et a/. (1999), Drug Metab. Disp. 27, 1165-1170; R.H. Lewinsky, et ai., (2005), Xenobiotica 35, 117-129). A drug metabolism inhibition calculation using Equation 1, provided above, yields a value of about 33% (0.5/1+0.5) which is in agreement with the approximately 30% increase in AUC observed by the addition of bioflavonoid.

The 49.5 mg Raloxifene-HCI tablets have the formula shown in Table 1 below:

Table 1

Blood samples were collected from the subjects before dosing and hourly for 8h after dosing, then at 10, 12, 16, and 24h, and thereafter at 24h intervals for 8 days. Plasma levels of raloxifene were determined by liquid chromatography tandem mass spectrometry analysis. A direct comparison of mean plasma raloxifene concentration over time for groups A and C is shown in Figure 1. Although administered as separate dosage forms, co-administration of raloxifene with bioflavonoids increased the bioavailability (AUC) of raloxifene by approximately 30% over the bioavailability of raloxifene administered alone. Furthermore, treatment C also resulted in a bioavailability which closely approximated the bioavailablity of Treatment B, a 60 mg tablet of raloxifene having the same percent composition as that shown in Table 1.

Table 2 shows the relative bioavailability of raloxifene-HCI alone compared with raloxifene-HCI plus bioflavonoid at the 90% confidence interval.

EXAMPLE 2. Improving Bioavailability of Fenofibrate

Like raloxifene, fenofibrate is also a highly lipophilic drug that is almost insoluble in water. Upon oral administration of ¹⁴C-labeled fenofibrate, approximately 60% of the labeled drug is excreted in the urine and about 25% is excreted directly in the feces. A. Weil, et a/. (1990), Drug Metab. Dispos. 18, 115-120. Metabolism of fenofibrate occurs initially via esterase activity in intestinal epithelial cells that yields the active drug, fenofibric acid, which is the form found in plasma. Fenofibric acid is further metabolized by conjugation to glucuronic acid and excreted in the urine. A. Weil, et a/. (1988), Drug Metab. Dispos. 16, 302-309. The site of fenofibric acid glucuronidation has not been directly studied. However, indirect evidence suggests at least a portion of the drug is conjugated to glucuronic acid in intestinal epithelial cells. In contrast to humans, glucuronidation of fenofibric acid is a very minor reaction in rats, which lack significant intestinal UGTs. A. Weil, et a/. (1988), Drug Metab. Dispos. 16, 302-309. These and other references concerning the activity of fibrate drugs suggest that at least a portion, and perhaps the majority, of fenofibric acid glucuronidation occurs presystemically in the intestinal epithelia. Therefore, methods that limit the glucuronidation of fenofibrate in intestinal epithelia, such as competitive inhibition for metabolizing enzymes, would increase the systemic bioavailability of the drug. Although the invention is illustrated and described herein with reference to specific embodiments, the invention is not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the invention. For example, the metabolizing enzymes targeted for competitive inhibition may include cytochrome P450 isozymes, for which bioflavonoids would also be effective as competitive inhibitors.

Claims

What is Claimed:

1. A method for improving the bioavailability of a drug that is metabolized by one or more metabolizing enzymes in the intestinal epithelium or in the liver, comprising orally administering to a patient in need thereof a therapeutic amount of the drug in combination with a suitable competitive inhibitor in an amount sufficient to effectively compete with the drug for at least one metabolizing enzyme.

2. The method of claim 1, wherein the method comprises administering a composition comprising the drug and the competitive inhibitor.

3. The method of claim 1, wherein the method comprises sequential, contemporaneous administration of the drug and the competitive inhibitor in either order.

4. The method of claim 1 wherein the competitor inhibitor competes with the drug for the metabolizing enzyme, wherein the metabolizing enzyme is a UDP- glucuronosyltransferase (UGT).

5. The method of claim 4 wherein the metabolizing enzyme is selected from the group consisting of UGTl isoenzymes, UGT2 isoenzymes, and mixtures thereof.

6. The method of claim 5 wherein the metabolizing enzyme is selected from the group consisting of UGTlAlO, and UGT1A8, and mixtures thereof.

7. The method of claim 1, wherein the drug is a drug that, after oral ingestion, is glucuronidated by one or more of a U DP-g I ucuronosy (transferase selected from the group consisting of UGTl and UGT2 isoenzymes and mixtures thereof; and wherein the competitive inhibitor is administered in an amount sufficient to compete with the drug for the UGTl or UGT2 isoenzymes.

8. The method of claims 1 or 7, wherein the drug is a lipophilic drug.

9. The method of claim 1 or 7, wherein the drug is selected from the group consisting of raloxifene, fenofibrate, gemfibrozil, troglitazone, arzoxifene, sertraline, olanzapine, celecoxib, venlafaxine HCI, rosiglitazone, pioglitazone HCI, ondansetron, topiramate, lamotrigine, ramipril, carvedilol, ezetimibe, atomoxetine, desloratadine, mycophenolate mofetil, oxcarbazepine, tegaserod, bicalutamide, moxifloxacin, divalproex, and furosemide

10. The method of claim 9, wherein the drug is selected from the group consisting of raloxifene, arzoifene, troglitazone, and fenofibrate.

11. The method of claims 1 or 7, wherein the competitive inhibitor comprises a bioflavonoid.

12. The method of claim 11, wherein the bioflavonoid is selected from the group consisting of hersperidin, eriodictyl, quercetin, rutin, hesperitin, 7-hydroxyflavone, chrysin, apigenein, fisetin, naringenϊn, and genistein and mixtures thereof.

13. The method of claim 1 or 1, wherein a fold-Kj:fold-K_m ratio of the competitive inhibitor to the drug is in the range of from about 0.01 to about 50.

14. The method of claim 13, wherein the fold-Kj.-fold K_m ratio of competitive inhibitor to drug is in the range of about 0.02 to about 10.

15. The method of claim 13, wherein the fold-K,:fold K_m ratio of competitive inhibitor to drug is in the range of about 0.05 to about 5.