Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

• the present invention relates to a method for increasing the oral bioavailability of eletriptan which comprises co-administering eletriptan with a p-glycoprotein (p-gp) inhibitor.
• the invention further relates to compositions and kits comprising eletriptan and a p-gp inhibitor.
• Eletriptan is a potent and selective agonist for the vascular 5 ⁇ HT-
• eletriptan is predominantly metabolised by cytochrome P450-3A4 isozyme (CYP3A4). Therefore potent inhibition of this enzyme system by ketoconazole and erythromycin results in an increased systemic exposure and reduced clearance of eletriptan.
• the present invention is based, inter alia, on the results of a study to assess the safety, tolerability and pharmacokinetics of a single dose of eletriptan in the presence of a p-gp inhibitor, such as verapamil.
• Verapamil is a calcium ion influx inhibitor ('calcium channel blocker') having both systemic and coronary arteriodilator activity which is mainly used for the control of angina pectoris and hypertension.
• Kj 10 ⁇ M
• Verapamil is known to alter hepatic blood flow, which could also influence eletriptan pharmacokinetics, so hepatic blood flow was also evaluated in the study.
• the study was designed to provide additional clinical information on the effect of a moderate CYP3A4 inhibitor on eletriptan pharmacokinetics and help define the in vitro/in vivo drug interaction correlation.
• the study was to be used to provide information on the potential for pharmacokinetic interactions between eletriptan and other CYP3A4 inhibitors.
• a formulation of eletriptan which increased the drug's oral bioavailability and thus could be dosed at lower doses and yet provide in a more consistent manner the efficacy benefits of a higher dose.
• An especially useful formulation could provide rapid onset and consistent action using a lower dose and reducing drug interactions and side-effects because of more consistent delivery.
• a formulation which is, say, 50% more bioavailable could be dosed at 40mg and provide the same systemic exposure as currently available formulations when dosed at 60mg.
• MDR Multi-Drug Resistance
• P-gps are also present in many types of normal cells, including, as indicated, those of the intestinal epithelium.
• Intestinal epithelial cells lECs
• I ECs Intestinal epithelial cells
• the apical side of the I EC faces the intestinal lumen and the basolateral side faces the portal blood.
• Most drugs are absorbed passively, first crossing the lEC apical cell membrane and entering the I EC interior, then crossing the basolateral cell membrane, thus exiting the cell on the basolateral side, entering the extracellular space and ultimately partitioning into the portal bloodstream.
• P-gps are located on the apical cell membrane of the lEC and have the capacity to pump certain drugs out of the lEC back into the intestinal lumen. Thus lEC p-gps hinder the absorption of many drugs.
• the p-gps in lECs may also have a role in presenting drugs to the drug metabolising enzymes; it has been speculated that their purpose is to slow or prevent oral absorption of toxins.
• the p-gp efflux pump belongs to the superfamily of ATP-binding cassette (ABC) membrane transport proteins. P-gps exhibit low substrate specificity and transport many kinds of molecules.
• European Patent Application No. 0742722 broadly claims, inter alia, a method for increasing the bioavailability of an orally administered hydrophobic pharmaceutical compound, for example, cyclosporine (log e P 3.0), which comprises orally administering said compound concurrently with a bioenhancer comprising an inhibitor of a cytochrome P450-3A enzyme or an inhibitor of p-gp-mediated membrane transport.
• a bioenhancer comprising an inhibitor of a cytochrome P450-3A enzyme or an inhibitor of p-gp-mediated membrane transport.
• the invention provides eletriptan in combination with a p-gp inhibitor for use as a medicament by means of which the rate and extent of oral bioavailability of eletriptan are significantly improved.
• the invention further provides for the use of eletriptan in the preparation of a medicament combined with a p-gp inhibitor for the treatment of migraine and for the use of eletriptan in the preparation of a medicament for the treatment of migraine for administration to patients concomitantly receiving a p-gp inhibitor.
• compositions comprising eletriptan and a p-gp inhibitor and kits comprising separate compositions of each are also provided.
• Eletriptan can be employed in this invention in the form of its pharmaceutically acceptable salts including hydrates thereof. All such forms are within the scope of the invention.
• the eletriptan employed is preferably the hydrobromide salt disclosed, for example, in European Patent No. 0776323.
• Reference to "eletriptan" in terms of therapeutic amounts is to the free base, i.e. the non-salt, non-hydrated molecule.
• 'p-gp inhibitor' shall be understood to include the types of compounds which are known in the art as MDR proteins or p-gp inhibitors. These may include both pharmaceutically-active compounds and compounds considered non-pharmaceutical in the sense that, but for their p- gp inhibitory activity, they are therapeutically inactive.
• the term 'p-gp inhibitor' shall be understood to mean that more than one p-gp inhibitor, separately or together in a composition, can be co-administered with eletriptan.
• the terms 'MDR protein' and 'p-gp inhibitor' are interchangeable and include the totality of lEC and brain endothelial cell membrane pump proteins which expel drugs from these cells.
• a p-gp inhibitor/MDR protein interaction which enhances eletriptan bioavailability may operate by one or more of a variety of mechanisms. That is, as is well known in the art, it may be a competitive inhibitor, a non- competitive inhibitor, an uncompetitive inhibitor, or operate by a mixed mechanism.
• Whether such an inhibitor can affect eletriptan efflux depends, inter alia, upon (1) the relative affinities of eletriptan and the inhibitor for p- gp/MDR, (2) the relative aqueous solubilities of eletriptan and the inhibitor, because this will affect the concentration of the two at the pump in vivo when they are in competition, (3) the absolute aqueous solubility of the inhibitor, because it must achieve a sufficient concentration at the pump in vivo to effectively inhibit the pump, and (4) the dose of the inhibitor.
• a 'p-gp/MDR inhibitor is any compound which improves the systemic exposure of eletriptan, when eletriptan is dosed by the buccal or oral route, and which is effluxed by and/or inhibits one or more of the drug efflux proteins of the intestinal epithelial cells.
• Evidence of efflux and/or inhibition may be obtained in an in vitro test such as a test of competition with, or inhibition of, eletriptan efflux in a cell culture model for intestinal epithelial cells.
• the Caco-2 cell model is one such model.
• this definition of a 'p-gp/MDR inhibitor 1 applies to any p-gp/MDR inhibitor, regardless of whether or not said p-gp/MDR inhibitor is a drug, that is, pharmaceutically active other than as a p-gp inhibitor.
• references to “administration”, “administering”, “dosage” and “dosing” means oral administration.
• Co-administration of a combination of eletriptan and a p-gp inhibitor means that the two components can be administered together as a composition or as part of the same unitary dosage form. Co-administration also includes administering eletriptan and a p-gp inhibitor separately, but as part of the same therapeutic regimen. The two components, if administered separately, need not necessarily be administered at essentially the same time, although they can be if so desired. Thus co-administration includes, for example, administering eletriptan plus a p-gp inhibitor as separate dosages or dosage forms, but at the same time. Co-administration also includes separate administration at different times and in any order.
• eletriptan may be dosed at (1) the same level at which it would be dosed in the absence of a particular p-gp inhibitor if the goal is to increase the intracellular level of eletriptan; or (2) at a decreased level relative to the normal level at which it would be dosed in the absence of the p-gp inhibitor.
• the eletriptan may also be administered at an intermediate level between the two dosage values.
• Eletriptan is presently administered orally as an acute treatment in a single dose of 20, 40, or 80mg.
• any oral dosage form of eletriptan including suspensions, tablets, capsules and unit dose packets (referred to in the art as "sachets") may be employed, for example, as described in the latest Physicians' Desk Reference.
• eletriptan may, for example, be administered as a single dose with verapamil to abort a migraine attack; a second dose may be required if the migraine recurs within 24 hours.
• eletriptan/p-gp inhibitor dose regimens are possible. Useful dose regimens are those which increase the bioavailability or brain penetration or other tissue levels of eletriptan.
• eletriptan and a p-gp inhibitor are dosed at the same time, i.e. within 15 minutes of each other. Oral bioavailability can be assessed by measuring AUC or C ma ⁇ , both parameters well known in the art.
• AUC is a determination of the Area Under the Curve plotting the serum or plasma concentration of drug along the ordinate (Y-axis) against time along the abscissa (X-axis).
• the values for AUC represent a number of values taken from all the subjects in a patient test population and are therefore mean values averaged over the entire test population.
• C ma ⁇ is an abbreviation for the maximum drug concentration achieved in the serum or plasma of the test subject.
• a p-gp inhibitor is co-administered with eletriptan in such an amount that the oral bioavailability of the eletriptan, as measured by AUC, is increased by at least 25%, that is, to an absolute bioavailability of at least 62.5%.
• a p-gp inhibitor is co-administered in such an amount that the oral bioavailability of the eletriptan, as measured by AUC, is increased by at least 50%, that is, to an absolute bioavailability of at least 75%.
• a p-gp inhibitor is co-administered in such an amount that the oral bioavailability of the eletriptan, as measured by AUC, is increased by at least 100%, that is, to an absolute bioavailability of 100%.
• a p-gp inhibitor is co- administered with eletriptan in such an amount that the oral bioavailability of the eletriptan, as measured by C ma ⁇ , is increased by at least 50%.
• a p-gp inhibitor is co-administered in such an amount that the oral bioavailability of the eletriptan, as measured by C m a ⁇ , is increased by at least 100%.
• a p-gp inhibitor is co-administered in such an amount that the oral bioavailability of the eletriptan, as measured by Cmax, is increased by at least 200%.
• the p-gp inhibitor may, in one aspect, be widely chosen from numerous compounds, including compounds which are non-pharmaceutical in the sense that they are not known to exhibit any therapeutic effect and/or which, but for their p-gp inhibitory activity, would be considered therapeutically inactive.
• the p-gp inhibitor may be selected from compounds which are themselves drugs and which, in addition to their known therapeutic function(s), also inhibit p-gp.
• p-gp inhibitors which are generally considered to be non- pharmaceutical and/or therapeutically inactive include those listed in Table I. These inhibitors may be dosed at doses of 25mg to 3g, preferably 50 mg to 2g, more preferably 50mg to 1g.
• the non-pharmaceutical p-gp inhibitor is selected from the class of polymers which are block copolymers of polypropylene oxide) and poly(ethylene oxide).
• block copolymers are available under the registered trademark PluronicTM from BASF.
• Preferred polymers include PluronicTM L43, L61 , L62, L64, L81 , L92, L101 , P85, P103, P104 and P123, all available from BASF Corp., Parsippany, NJ. Of these, PluronicTM L61 , L62, L64, L81, L92, P85, P103 and P104 are particularly preferred.
• the compositions of these polymers can readily be obtained from BASF Corp.
• the non-pharmaceutical p-gp inhibitor is a surfactant selected from the class of non-ionic surfactants.
• examples are the PEO esters of oleic acid, preferably those wherein the PEO content is in the range 20-30 PEO units per molecule.
• Examples also include PEO esters of stearic acid, preferably those containing 10-35 PEO units per molecule.
• Useful surfactant p-gp inhibitors include polyoxyethylene ethers (e.g. Brij series), para-t-octylphenoxypolyoxyethylenes (e.g. Triton X-100), nonylphenoxypolyoxyethylenes (e.g.
• non-ionic surfactant p-gp inhibitors have a hydrophile- lipophile balance (HLB) number greater than about 13.
• p-gp inhibitors which are drugs having a therapeutic function other than p-gp inhibition include those listed in Table II:
• the drugs listed in Table II may be administered in their conventional dosage amounts, for example, as given in the latest Physicians' Desk Reference.
• the pharmaceutically-active p-gp inhibitor is an antimalarial drug such as chloroquine, hydroxychloroquine, quinidine, or quinine; an anti-AIDs drug such as nelfinavir, saquinavir, ritonavir, or indinavir; an antibiotic such as cefoperazone or ceftriaxone; an antifungal such as itraconazole; an immunosuppressant such as cyclosporine; or a calcium channel blocker such as verapamil. Verapamil is especially preferred.
• the invention further provides pharmaceutical compositions comprising eletriptan and a p-gp inhibitor.
• the components can be administered together, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
• eletriptan and a p-gp inhibitor can be administered orally, buccally, or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions, or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
• Eletriptan and a p-gp inhibitor may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations of eletriptan and a p-gp inhibitor may be coated or uncoated.
• Such solid pharmaceutical compositions may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato, or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
• excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato, or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates
• a formulation of the tablet could typically contain between about 0.1 mg and 200mg of eletriptan and from 20mg to 1000mg of a p-gp inhibitor, whilst tablet fill weights may range from 50mg to 1000mg.
• An example of a formulation for a 20mg tablet is illustrated below:
• the tablets are manufactured by a standard process, for example, direct compression or a wet or dry granulation process.
• the tablet cores may be coated with appropriate overcoats.
• Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules.
• Preferred excipients include lactose, starch, a cellulose, milk sugar, or high molecular weight polyethylene glycols.
• eletriptan and a p-gp inhibitor may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, or combinations thereof.
• Eletriptan and a p-gp inhibitor may also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly, or subcutaneously, or they may be administered by infusion or needleless injection techniques.
• parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
• the aqueous solutions may be suitably buffered, preferably to a pH of from 3 to 9.
• tablets or capsules of eletriptan and a p-gp inhibitor may contain from 0.1 mg to 200mg of eletriptan for administration singly or two or more at a time, as appropriate.
• the physician will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
• the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of the invention.
• the skilled person will appreciate that, in the treatment of certain conditions such as a migraine attack, eletriptan and a p-gp inhibitor may be taken as a single dose as and when needed.
• Eletriptan and a p-gp inhibitor can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser, or nebuliser, with or without the use of a suitable propellant, e.g.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• the pressurised container, pump, spray, atomiser, or nebuliser may contain a solution or suspension of the active compound, e.g.
• Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of eletriptan, a p-gp inhibitor and a suitable powder base such as lactose or starch.
• eletriptan and a p-gp inhibitor can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment, or dusting powder. Eletriptan and a p-gp inhibitor may also be administered dermally or transdermally, for example, by means of a skin patch. They may also be administered by the pulmonary or rectal routes.
• Eletriptan and a p-gp inhibitor may also be administered by the ocular route.
• they may be formulated as micronised suspensions in isotonic, pH-adjusted, sterile saline or, preferably, as solutions in isotonic, pH- adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
• they may be formulated in an ointment such as petrolatum.
• eletriptan and a p-gp inhibitor may be formulated as a suitable ointment containing eletriptan suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• ком ⁇ онентs may be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• Eletriptan and a p-gp inhibitor may also be used in combination with a cyclodextrin.
• Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability properties of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
• the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent, or solubiliser.
• Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in International Patent Application Nos. WO-A-91/11172, WO-A- 94/02518 and WO-A-98/55148.
• the present invention also relates to treatment with a combination of eletriptan and a p-gp inhibitor which may be co-administered separately; the invention therefore also provides a kit comprising separate pharmaceutical compositions of each.
• a kit according to the invention comprises (1) a therapeutically effective amount of a composition comprising eletriptan and a pharmaceutically acceptable carrier, diluent, or excipient in a first dosage form;
• composition comprising a compound which is a p-gp inhibitor and a pharmaceutically acceptable carrier, diluent, or excipient in a second dosage form;
• the relative amounts of (1) and (2) are such that, when co-administered separately, the bioavailability of eletriptan is increased.
• the kit comprises a container for containing the separate compositions, such as a divided bottle or a divided foil packet, wherein each compartment contains a plurality of dosage forms (e.g. tablets) comprising (1 ) or (2).
• the kit may contain separate compartments each of which contains a whole dosage itself comprising separate dosage forms.
• kits are blister pack wherein each individual blister contains two (or more) tablets or capsules comprising one (or more) tablet(s) or capsule(s) of pharmaceutical composition (1) and one (or more) tablet(s) or capsule(s) of pharmaceutical composition (2).
• the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g. oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desirable.
• Caco-2 cell assay of the type described, for example, in Kim et al, J. Clin. Invest. 101 , 289-294 (1998), and in Example 1.
• Caco-2 cells are colon carcinoma cells which are considered in the art to be a reasonable model for the intestinal epithelium.
• Caco-2 cell monolayers were grown on permeable 24 well filter supports (1 ⁇ m poresize) and used at Day 15-28.
• the permeability of eletriptan was examined in both the apical and basolateral direction (absorptive) and basolateral to apical (secretory) direction at different concentrations and in the presence of p-gp inhibitors.
• p-gp inhibitors verapamil, ketoconazole and erythromycin were included, they were added to both the donor and acceptor chambers at concentrations of 100, 50 and 100 ⁇ M respectively. In these studies, a concentration of 10 ⁇ M eletriptan was used. Appropriate controls containing no inhibitor were included.
• Eletriptan is a substrate for the p-gp efflux transporter. Eletriptan exhibits a higher secretory flux (basolateral-to-apical; B -> A) than absorptive flux (apicai-to-basolateral; A -> B ) at low concentrations which is consistent with p-gp-mediated efflux. Larger absorptive P app values are found at higher concentrations due to saturation of the p-gp.
• Plasma eletriptan concentrations were assayed up to 48 hours post-eletriptan on Day 6. Concentrations were determined by specific reversed phase high performance liquid chromatography (hplc) with ultraviolet detection with a calibration range of 0.5 to 250ng/ml.
• Plasma samples (2.5ml) were collected at 0, 0.17, 0.33, 0.5, 1 , 2, 4, 6, 8, 12 and 24 hours after dosing and centrifuged. The resulting plasma samples were deep frozen until analysed for eletriptan by hplc with electrochemical detection. Rapid attainment and high peak concentrations of eletriptan were observed with T ma ⁇ values in the range 1.0 and 1.7 hours and C max values in the range 7 to 15ng/ml.

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