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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
  • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

• the invention relates to modulating vitamin levels in animals, particularly levels of endogenous storage forms of tocopherol (Vitamin E), retinol (Vitamin A) or Vitamin K1 by administration of phosphate derivatives.
• tocopherol and tocopheryl phosphate Whilst the following discussion concerns tocopherol and tocopheryl phosphate (TP), it is to be understood that this is merely illustrative and that the invention is not limited to tocopherol or TP but that the invention also similarly relates to retinol and vitamin K1 and their storage and transport forms.
• Vitamin E is widely recognised as an anti-oxidant of considerable biological importance. It is a potent free radical scavenger with a vital role in the maintenance of cellular integrity through its capacity to protect the polyunsatu rated fatty acyl moieties of phospholipids in biological membranes and plasma lipoproteins.
• Vitamin E consists of the group of isoprenoids know as 'tocopherols' which provide benefits to the health and well-being of humans and animals.
• Several different tocopherols having Vitamin E activity are known, the most active and abundant being ⁇ -tocopherol.
• the supplements should have adequate stability, solubility, permeability and bioavailability.
• Free tocopherol is not stable and therefore not suitable as a bioavailable delivery form of Vitamin E.
• derivatisation has long been recognised as an important means of increasing stability and bioavailability of tocopherol, but it is generally accepted that absorption of these derivatives has still been low.
• Tocopherol organic esters such as tocopheryl acetate or tocopheryl succinate are examples of such derivatised species which are currently in widespread commercial use. These esters are cheap to produce and more stable than free tocopherol.
• tocopherol derivatives should be capable of converting to the biologically active species after they have been absorbed into the systemic circulation of a human or animal subject.
• Formulators believed that the free form of tocopherol was biologically active and thus believed that when the pancreatic esterase and lipase activity released free tocopherol from the organic esters of tocopherol in the small intestine lumen, the body's levels of Vitamin E were increased.
• Tocopherol acetate has been favoured as a Vitamin E dietary supplement of the prior art because it reportedly causes an immediate, readily measurable increase in plasma free tocopherol levels.
• Formulators who have been attempting to increase the water solubility of tocopherol derivatives have prepared formulations containing TP as it is much more water soluble than organic esters of tocopherol. While TP has been used as a water soluble source of Vitamin E in vitro, it has not previously been commonly • used as a suitable in vivo source of Vitamin E because the phosphate group is a substrate of phosphorylases, is resistant to passive transport, and therefore considered to interfere with absorption.
• Vitamin E supplements containing either tocopheryl acetate or tocopheryl phosphate have aimed to provide a recommended daily intake of 7 - 15 mg/day per person of free tocopherol in the body. Supplements have contained 200 - 600 mg as this amount is considered to be innocuous in adult humans, although there is limited evidence of this.
• Paradoxically, as well as being a potent free radical scavenger ⁇ -tocopherol is also a pro-oxidant and a potential source of free radicals which would cause damage to the body. Free tocopherol is pro-oxidant at high concentrations so it is unlikely that this is the biological storage or transport form within the body.
• tocopherol, retinol and vitamin K1 are their respective phosphate derivatives. These phosphate derivatives are not typically a source of free radicals. Surprisingly, the present inventors have found that administering phosphate derivatives of tocopherol, retinol or vitamin K1 to an animal can provide therapeutically useful levels of tocopherol, retinol or vitamin K1 in storage and transport forms.
• the present invention provides a method for increasing levels of a storage form of a vitamin selected from the group consisting of tocopherol, retinol, vitamin K1 and mixtures thereof in a target tissue of a subject, the method comprising administering to the subject an effective amount of a phosphate derivative of the vitamin so as to cause an accumulation of stored vitamin in the target tissue.
• the vitamin is tocopherol.
• the subject is an animal, more preferably the animal is a human.
• the target tissue is liver because it is the storage organ of preference and the generation site of lipoprotein cholesterol. It is also known that there is Vitamin E activity in the skin and TP is important in skin metabolism. Vitamin E may also be important for adipose tissue where it may protect against degradation of unsaturated fats. Vitamin E may also be important in the brain.
• the increased levels of the stored vitamin(s) result in potentially therapeutic levels of the vitamin(s) in the animal.
• the present invention is particularly suitable for increasing the storage levels of the vitamins to be of therapeutic value.
• Increased levels of vitamins, particularly tocopherol can have uses in the treatment of inflammatory diseases such as, but not limited to, coronary diseases, atherosclerosis and diabetes and a number of diseases affected by tocopherol, such as cancer where tocopherol affects cell adhesion, and foetal development.
• inflammatory diseases such as, but not limited to, coronary diseases, atherosclerosis and diabetes
• tocopherol a number of diseases affected by tocopherol, such as cancer where tocopherol affects cell adhesion, and foetal development.
• vitamin levels may assist treatment of alzheimers.
• Therapeutic levels of the vitamins would typically be in the order of at least about 50% increase of the levels usually stored in healthy or normal tissue. Preferably, the levels are increased by at least about 100%, more preferably at least about 200%, that is, about 2 to 3 times normal plasma or tissue levels.
• higher levels of vitamins can then be released in a number of ways to provide potentially higher doses of biologically available vitamin to organs or tissue in the body as required.
• the present invention may also be suitable for treating or overcoming problems with subjects unable to acquire or utilise vitamins by normal dietary uptake or processing.
• the ability to increase storage levels may also be useful to overcome consequences of periods of low or poor dietary intake.
• Tocopherol is used in three forms in the body, being
• the increased storage forms acts as a source of tocopherol, retinol or vitamin K1 to tissue, organs or cells of the subject.
• the present inventors have found that at least about 3 mg/kg (at least about 240 mg in an 80 kg adult), typically from about 3 to 50 mg/kg of the phosphate derivative of the vitamin is required to increase storage levels to a beneficial amount. More preferably, 3 to 30 mg/kg is provided. More preferably, at least 10 mg/kg body mass of tocopherol provided orally as tocopheryl phosphate has been found suitable to achieve a level of 68% absolute bioavailability. This is significantly more than the recommended daily intake (RDI) of 7-15 mg/day for a normal person.
• RDI recommended daily intake
• the dosage may be achieved by administering the phosphate derivative of the vitamin(s) in one dose or may be administered over a period of minutes, hours or days to achieve the required stored amount of the vitamin(s).
• the phosphate derivative of the vitamin can be given by any suitable route such as orally or parenterally.
• the present invention provides a method for alleviating or treating a subject suffering a condition responsive to a vitamin treatment, the method comprising administering to a subject in need of such treatment an amount of a phosphate derivative of the vitamin selected from the group consisting of tocopherol, retinol, vitamin K1 and mixtures thereof effective to cause an accumulation of a therapeutic amount of tocopherol, retinol vitamin K1 or a mixture thereof in a tissue of the subject.
• the conditions expected to be responsive to a vitamin treatment are inflammatory diseases such as, but not limited to, coronary diseases, artherosclerosis and diabetes and a number of diseases affected by tocopherol, such as cancer where tocopherol affects cell adhesion, and foetal development.
• inflammatory diseases such as, but not limited to, coronary diseases, artherosclerosis and diabetes and a number of diseases affected by tocopherol, such as cancer where tocopherol affects cell adhesion, and foetal development.
• the vitamin is tocopherol.
• the subject is an animal, more preferably the animal is a human.
• the target tissue is liver as this tissue can be used to indicate that there are adequate stores for the various ubiquitous metabolic activities in different tissues.
• the phosphate derivative of the vitamin can be given by any suitable route such as orally or parenterally.
• the present inventors have found that at least about 3 mg/kg (at least about 240 mg in an 80 kg adult), typically from about 3 to 30 mg/kg of the phosphate derivative of the vitamin is required to increase storage levels to a beneficial amount which can result in therapeutic levels of the vitamin(s). More preferably, about 10 mg/kg body mass of tocopherol provided orally as tocopheryl phosphate has been found suitable to achieve a level of 68% absolute bioavailability. This is significantly more than the recommended daily intake (RDI) of 7-10 mg/day for a normal person.
• RDI recommended daily intake
• the present invention provides use of an effective amount of a phosphate derivative of a vitamin selected from the group consisting of tocopherol, retinol, vitamin K1 and mixtures thereof in the manufacture of a supplement for causing an accumulation of stored vitamin in the target tissue of an animal.
• the present invention provides use of an effective amount of a phosphate derivative of a vitamin selected from the group consisting of tocopherol, retinol, vitamin K1 and mixtures thereof in the manufacture of a medicament for alleviating or treating a subject suffering a condition responsive to a vitamin treatment.
• phosphate derivatives of the vitamin is used herein to refer to the acid forms of phosphorylated tocopherol, retinol or vitamin K1 , salts of the phosphates including metal salts such as sodium, magnesium, potassium and calcium and any other derivative where the phosphate proton is replaced by other substituents such as ethyl or methyl groups or phosphatidyl groups.
• Phosphatidyl derivatives are amino alkyl derivatives of organic phosphates. These derivatives may be prepared from amines having a structure of R ⁇ R 2 N(CH 2 ) n OH wherein n is an integer between 1 and 6 and Ri and R 2 may be either H or short alkyl chains with 3 or less carbons. Ri and R 2 may be the same or different.
• the phosphatidyl derivatives are prepared by displacing the hydroxyl proton of the electron transfer agent with a phosphate entity that is then reacted with an arnine, such as ethanolamine or N,N' dimethylethanolamine, to generate the phosphatidyl derivative of the electron transfer agent.
• a basic solvent such as pyridine or triethylamine with phosphorous oxychlohde to prepare the intermediate which is then reacted with the hydroxy group of the amine to produce the corresponding phosphatidyl derivative, such as P cholyl P tocopheryl dihydrogen phosphate.
• complexes of phosphate derivatives of the vitamins may also be utilized where additional properties such as improved stability or deliverability may be useful.
• the term "complexes of phosphate derivatives of the vitamin” refers to the reaction product of one or more phosphate derivatives of tocopherol, retinol or vitamin K1 and mixtures thereof with one or more complexing agents selected from the group consisting of amphoteric surfactants, cationic surfactants, amino acids having nitrogen functional groups and proteins rich in these amino acids as disclosed in international patent application no PCT/AU01/01476.
• the preferred complexing agents are selected from the group consisting of arginine, lysine and tertiary substituted amines, such as those according to the following formula:
• R 1 is chosen from the group comprising straight or branched chain mixed alkyl radicals from C6 to C22 and carbonyl derivatives thereof;
• R 2 and R 3 are chosen independently from the group comprising H, CH 2 COOX, CH 2 CHOHCH 2 SO 3 X, CH 2 CHOHCH 2 OP0 3 X, CH 2 CH 2 COOX, CH 2 COOX, CH 2 CH 2 CHOHCH 2 SO 3 X or CH 2 CH 2 CHOHCH 2 OPO3X and X is H, Na, K or alkanolamine provided R 2 and R 3 are not both H; and wherein when R 1 is RCO then R 2 may be CH 3 and R 3 may be (CH 2 CH 2 )N(C 2 H 4 OH)-H 2 CHOPO 3 or R 2 and R 3 together may be N(CH 2 ) 2 N(C 2 H 4 OH)CH 2 COO-.
• Preferred complexing agents include arginine, lysine or lauryliminodipropionic acid ' where complexation occurs between the alkaline nitrogen center and the phosphoric acid ester to form a stable complex.
• the administration of phosphate derivatives of the vitamin to provide a 'therapeutic effect' includes administration to achieve a curative, preventative or other beneficial health effect.
• administration to a subject may be undertaken to treat a deficiency of the vitamin, to ameliorate or cure a disease or disorder, to ameliorate or remove the symptoms of the disease or disorder, or to increase the subject's plasma and tissue level of the vitamin to provide a beneficial effect.
• the phosphate derivative of the vitamin may be administered to humans or animals through a variety of dose forms such as supplements, enteral feeds, parenteral dose forms, suppositories, nasal delivery forms, dermal delivery including patches, creams, and any other delivery system capable of supplementing the natural storage and transport form of the electron transfer agent.
• dose forms such as supplements, enteral feeds, parenteral dose forms, suppositories, nasal delivery forms, dermal delivery including patches, creams, and any other delivery system capable of supplementing the natural storage and transport form of the electron transfer agent.
• the phosphate derivative of the vitamin may be administered by an orally or parenterally administered dose form.
• these include, tablets, powders, chewable tablets, capsules, oral suspensions, suspensions, emulsions or fluids, children's formulations, enteral feeds, nutraceuticals, and functional foods.
• the dose form may further include any additives routinely used in preparation of that dose form such as starch or polymeric binders, sweeteners, coloring agents, emulsifiers, coatings and the like.
• additives routinely used in preparation of that dose form such as starch or polymeric binders, sweeteners, coloring agents, emulsifiers, coatings and the like.
• Other suitable additives will be readily apparent to those skilled in the art.
• the dose form has an enteric coating as disclosed in international patent application PCT/AU01/01206.
• the dose form is a topical formulation as disclosed in international patent application PCT/AU02/01003.
• endogenous refers to a vitamin occurring in the body as the result of ingestion from a diet with no supplementation of the vitamin or its derivatives, and where only typical metabolic processes transform the dietary vitamin.
• Figure 1 Calibration curve for TP vs T 2 P using ESMS.
• Figure 2 GCMS of methylated liver extract and TP standard.
• Figure 3 Example of TP ESMS spectra.
• Figure 4 Example of liver extract ESMS spectra.
• ⁇ -tocopheryl phosphate the monophosphate ester of ⁇ -tocopherol, ⁇ - tocopheryl phosphate, is present in significant quantities (8-147 ⁇ g/g) in a range of biological tissues.
• ⁇ -Tocopheryl phosphate is resistant to oxidation and is thus inactive as an anti-oxidant; it is also resistant to acid and alkaline hydrolysis so that it cannot be detected by the standard assays for Vitamin E.
• the discovery of this storage form of Vitamin E heralds the need for a reassessment of the role of this essential vitamin in the body.
• TP as a nascent storage form is not a source of free radicals in marked contrast to free tocopherol which is an excellent source of undesirable free radicals or pro-oxidant at high concentrations.
• Oxidation with active phosphorylation of adenosine diphosphate for example, is known suggesting that ⁇ -tocopheryl phosphate may be a reducing agent capable of producing phosphorylated secondary messengers. This would account for the non-antioxidant roles ascribed to tocopherol.
• ⁇ -tocopheryl phosphate is stored in the lipoprotein environment in association with a lipophilic protein or as a glycerophosphate derivative.
• the proximity of a free radical or the generation of an oxidative environment stimulates the dephosphorylation of ⁇ - tocopheryl phosphate and the release of free ⁇ -tocopherol.
• excess antioxidant, ( ⁇ -tocopherol) is drawn back into storage by phosphorylation. This conservative strategy avoids pro-oxidation.
• This proposed mode of action for ⁇ -tocopheryl phosphate may also apply to other lipophilic bioactive compounds and provide a new explanation for its function in vivo.
• Vitamin E the storage form of Vitamin E was investigated in various tissues.
• the standard analytical methodology for the detection of ⁇ -tocopherol in tissue samples and foodstuffs normally includes a hydrolysis step as part of the extraction process.
• the hydrolysis ensures that ⁇ -tocopheryl esters, such as added ⁇ -tocopherol acetate, are converted to free ⁇ -tocopherol prior to analysis.
• ⁇ -tocopheryl phosphate is resistant to all of the alkaline and acid hydrolysis conditions encountered in these procedures and is consequently not included with free ⁇ -tocopherol in typical analyses. Indeed, refluxing ⁇ -tocopheryl phosphate under strongly alkaline or acidic conditions for extended periods in excess of 24 hours does not lead to any cleavage of the phosphate bond. We have been unable to discover conditions under which ⁇ -tocopheryl phosphate can be hydrolysed to yield free ⁇ -tocopherol. ⁇ -Tocopheryl phosphate has also proven to be resistant to oxidation and does not give a positive colour test under conditions of the standard colorimetric ⁇ -tocopherol analysis.
• GCMS Gas chromatography/mass spectrometry
• ⁇ -tocopheryl phosphate could not be detected, which suggests that it is associated with a protein or other some other compound; for example, the ⁇ -tocopheryl phosphate may be present as a glycerophosphate or similar ester, and that hydrolysis is required to liberate free ⁇ -tocopheryl phosphate.
• the hydrolysate was then washed with hexane to remove all of the organic soluble material. Free ⁇ -tocopherol was removed at this stage and could be readily analysed using standard techniques; ⁇ -tocopheryl phosphate was present as the potassium salt, and being water soluble was not extracted. Acidification of the aqueous layer converted the ⁇ -tocopheryl phosphate to the free acid, which was readily extracted into hexane.
• ⁇ -tocopheryl phosphate has been detected in pig, guinea pig, chicken and rat liver, and in human, pig and guinea pig adipose tissue. Liver and adipose have been reported to be the two main storage sites for ⁇ -tocopherol and it is therefore not surprising that ⁇ -tocopheryl phosphate is also present in these tissues. Our results indicate that the ⁇ -tocopheryl phosphate makes up a significant proportion of the total ⁇ -tocopherol present. TP has hitherto been considered to be unable to be deposited directly in tissues where it can remain as a storage form of tocopherol. However, the following example illustrates the detection of ingested TP in human and animal tissue.
• T 2 P ditocopheryl phosphate
• the methylated liver extract and TP standard were analysed using a Shimadsu GCMS-QP5000 Gas Chromatograph Mass Spectrometer incorporating a Shimadsu AOC-20i Auto Injector.
• One ⁇ l of sample was injected onto a 15m SGE.BP1 capillary column, with a thickness of 0.25 ⁇ m and an internal diameter of 0.25 mm utilising a temperature program from 260°C up to 300°C ramping at 3°C per minute.
• the injector and interface temperatures were both set at 300°C.
• the carrier gas used was helium, the column inlet pressure was set at 156 kPa and the total flow was 144 ml/min, thus presenting a column flow of 2.4 ml/min with a linear velocity of 86.5 cm/sec.
• the samples were run in split mode with a split ratio of 56:1.
• the detector gain for this acquisition was set at 1.5 kVolts.
• TP in Rat Liver Non-treated rat livers were used to extract, detect and quantitate the amount of naturally occurring TP.
• Fresh livers from Sprague-dawley and Wistar rats (aged between 10 to 11 weeks old, weighing approximately 120-180 grams) were used for each extraction.
• TP has also been detected in human abdominal fat, Guinea Pig and rat adipose tissue, porcine and guinea pig liver of humans and animals which have not been administered TP.
• Table 1 outlines the quantity of TP detected in each organ.
• This example investigates whether tocopheryl phosphate levels in storage sites are increased after tocopheryl acetate and tocopheryl phosphate were administered.
• Livers were be extracted according to the method below. The extracts will be analyzed and quantitated for TP ( ⁇ g) content by ESMS. Any tissue samples left over at the end of the study was kept frozen at -80 °C. Liver extraction
• liver was homogenized in 10 ml dichloromethane (analytical grade). Add 0.1 mg tocopheryl diphosphate (internal standard). Homogenize sample for 2 min, centrifuge and remove upper layer and evaporate under nitrogen. Add 9 ml KOH (2M) and stir for 1 hr at room temperature (or 20 min at 80 C). Add 10 ml hexane, shake and remove upper layer. Add 10 ml HCI (2M) and shake. Add 10 ml hexane to the solution and shake and remove upper layer. Evaporate top layer to dryness.
• TP was administered by IV to provide a value for absolute bioavailability.
• the amounts in brackets are percentages when compared with the IV value.
• TP has higher bioavailability than tocopheryl acetate because the transformation to phosphate is not required
• Table 4 shows the results of TP analysis in chicken fat, muscle and eggs.
• TP farnesoid TP

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