WO2006072203A1 - Inhibiteur ou promoteur de l’uridinediphosphate-glucuronosyltransferase2b (ugt2b) - Google Patents

Inhibiteur ou promoteur de l’uridinediphosphate-glucuronosyltransferase2b (ugt2b) Download PDF

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WO2006072203A1
WO2006072203A1 PCT/CN2005/002167 CN2005002167W WO2006072203A1 WO 2006072203 A1 WO2006072203 A1 WO 2006072203A1 CN 2005002167 W CN2005002167 W CN 2005002167W WO 2006072203 A1 WO2006072203 A1 WO 2006072203A1
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Prior art keywords
pharmaceutical composition
ugt2b
acid
nalbuphine
composition according
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PCT/CN2005/002167
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English (en)
Chinese (zh)
Inventor
Oliver Yoa-Pu Hu
Cheng-Huei Hsiong
Mei-Ting Wang
Li-Heng Pao
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Oliver Yoa-Pu Hu
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Priority claimed from US11/028,615 external-priority patent/US20060040875A1/en
Application filed by Oliver Yoa-Pu Hu filed Critical Oliver Yoa-Pu Hu
Priority to CA2593140A priority Critical patent/CA2593140C/fr
Priority to JP2007549784A priority patent/JP5133064B2/ja
Publication of WO2006072203A1 publication Critical patent/WO2006072203A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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

Definitions

  • the present invention relates to the field of biology, and in particular to an effective UGT2B inhibitor for increasing the bioavailability of a drug; and the present invention particularly relates to a UGT2B promoter for promoting the detoxification function of an individual.
  • phase I reaction The process of drug metabolism in the human body, especially for drugs with high fat solubility, can be basically divided into two stages of biotransformation: the first phase reaction (phase I reaction) is the original The fat-soluble molecule adds a functional group to make it a polar molecule; the second phase reaction produces a highly polar product by conjugation to rapidly metabolize the drug. Excluded from urine or feces.
  • UDP Uridine diphosphate
  • UGTs are one of the major metabolic enzymes in the second phase of the human body. It has been confirmed that UGTs have more than 110 isoenzymes.
  • UGTs catalyze the binding of UDP-glucuronic acid (UDPGA) to the chemical groups of endogenous fat-soluble compounds, for example, hydroxyl (hydroxy), sulfonyl, On the carboxylic acid, amine or amide, forms 0-glucuronidation. N-glucuronidation and S-glucuronidation (S) -glucuronidation) (King et al., 2000, Curr. Drug Metab., 1 (2): 143-61), in order to increase the polarity of the fat-soluble compound.
  • UDPGA UDP-glucuronic acid
  • S S-glucuronidation
  • UGTs also have a wide range of substrate specificity.
  • the compounds metabolized by UGT1A and UGT2B are not identical.
  • UGT1A is mainly metabolized such as estrone, 2-hydroxyestrone, 4-nitrophenol, 1-naphthol (1-naphthol).
  • phenolic compounds, and bilirubin are involved in this metabolism
  • UGT2B is a class of steroids such as androsterone and linoleic acid. Compounds ), and bile acids are involved in this metabolism.
  • UGTs can also convert certain compounds into higher biological activities, or in some cases. It is converted to toxic compounds, such as morphine, steroids, bile acids, and mid retinoids (see ore et al. (1983a) Life Sciences 32: 2989-2993; Vore et al. (1983b) Drug Metabolism Reviews 14:1005-1019; Abbott and Palmour (1988) Life Sciences 43:1685-. It is also reported in the literature that UGTs are involved in polycyclic aromatic hydrocarbons (polycyclic). Aromatic hydrocarbons, PAH) Activation of compounds such as heterocyclic aromatic amines ⁇ Munzel et al. (1996) Archives of Biochemistry and Biophysics, 355: 205-210; Bock et al. (1998) Advances in Enzyme Regulation, 38: 207- 222)
  • UGT exists in several tissues in the body, including liver, kidney, biliary tract, esophagus, stomach, intestine, rectum, ileum, jejunum, pancreas, breast, skin, lung, brain, etc., and the distribution of different UGTs in the body Also different, for example, UGT2B7 is present in the esophagus, liver, intestine, colon, kidney, pancreas, UGT1A1 is present in the liver, biliary tract, stomach, colon Tukey et al. (2000) Annu. Rev. Pharmacol. Toxicol., 40: 581 - 616. Review).
  • UGTs are also an important detoxification system in the human body. Except for endogenous fat-soluble compounds, exogenous fat-soluble compounds can have higher water solubility after acidification via glucuron, thereby increasing the elimination rate of exogenous fat-soluble compounds, Keep the body in a normal detoxification function.
  • UGTs which are abundant in the intestines and liver, have been shown to be one of the major enzymes that produce a first-pass effect after absorption. Drugs that undergo a first-pass effect will have low and variability in bioavailability.
  • UGT suppression Qi! J includes, for example, 7 silymarin ⁇ Venkataramanan et al. (2000) Dug. Metabolism and Disposition 28: 1270-1273), quinoline ⁇ Dong et al., 1999, Drug Metabolism & Disposition 27: 1423-1428), oltipraz (Vargas et al., 1998, Drug Metabolism & Disposition 26: 91-9 ⁇ ), which is tacrolimus ⁇ Zucker et al., 1999, Therapeutic Drug Monitoring 21:35-43) , octyl gallate , apigenin , imipramine , clozapine , acetaminophen and emodin Eraodin) (as mentioned above, 73 ⁇ 4 ⁇ 3 ⁇ 477 ⁇ 3 - corpus az/ija et al., 1999).
  • UGT inhibitors that can be used to increase the bioavailability of a drug must have at least three of the following characteristics: (1) No or only minimal pharmacological effects other than inhibition of UGTs (2) The inhibitory effect must be a reversible reaction. In other words, once the inhibitor is excreted or metabolized, the normal metabolic function of UGTs can be restored; and (3) the inhibitor should be effective enough to use the lowest The dose significantly reduces UGTs activity in the gut and liver.
  • US 6,121,234 discloses a method for promoting the bioavailability of an orally administered pharmaceutical compound in the gut of a mammal by using an essential oil comprising orally administering to the mammal
  • the pharmaceutical compound and an essential oil or an essential oil component are administered in a desired therapeutic amount, wherein the essential oil or the essential oil component has at least a concentration of less than 0.01% by weight or less.
  • Activity at a 10% inhibition rate It is also disclosed in this U.S. patent that essential oils promote the bioavailability of drugs by inhibiting cytochrome P450.
  • 150 kinds of formal Chinese herbal compound prescriptions contain 150 kinds of squares (71. 4%). Licorice is most frequently used, while the frequency of use of ginger and jujube is 42.9% and 31.9% respectively.
  • the most frequently used traditional Chinese medicine is cited as licorice ( 71. 4%), ginger (42, 9%), medlar (35.2%), peony (32.9%), jujube (31.9%) and cinnamon (29.5%).
  • UGT inhibitors such as: Chinese medicines rich in flavonoids.
  • ⁇ Scutellariae radix which contains baicalin, wogonin, baicalein, skull cap-flavon I and wogoin glucuronide, and artemisiae cpillaris herba, Capillarisin, cirsilineol, cirsimaritin, genkwanin, and rhamrcocitrin; and, for example, traditional Chinese medicines that are rich in terpenoids, such as , Alisporium tis rhizoma), which contains alisol monoacetate ⁇ ⁇ ⁇ ⁇ ⁇ (triterpenoids), Moutan radicis cortex), 3 ⁇ 4 contains paeonif lorin, oxypaeoniflorin and its benzepidine-derived Aconite ⁇ A
  • opiods drugs such as buprenorphine; nalbuphine, butorphanol
  • the receptors can show the dual effects of co-agents and antagonists, so they are also called narcotic agonist-antagonist analgesics.
  • nalbuphine is safer than traditional addictive analgesics and has excellent therapeutic effects.
  • Excipients in the group consisting of: stearyl alcohol, sodium caxboxymethyl-cellulose, glycerol, cetyl alcohol, 1, 3-propanediol (1,3- propylene glycol) And water.
  • the test drug is colchicine, which is mainly metabolized in the body via P_gp and CYP3A4.
  • colchicine was dissolved in 0.9% NaCl solution
  • colchicine was dissolved in 5% containing polyethylene glycol stearate 15 (solutol HS15).
  • solutol HS15 polyethylene glycol stearate 15
  • the experimental results showed that the highest blood solubility in the experimental group was significantly higher than that in the control group.
  • the clearance rate in the body is significantly less than 2 times.
  • polyethylene glycol stearate 15 (solutol HS15) significantly reduced the intrinsic clearance of colchicine. It is worth noting that in other literature reports, such surfactants destroy cell membranes and affect the normal physiological activity of cells (Silva et al., 2004), thereby changing the utilization of some cofactors in the catalytic reaction of enzymes. , or the interaction between the substance and the enzyme. However, at this concentration, polyethylene glycol stearate 15 (solutol HS15) was tested by light microscopy and there was no change in cell integrity. Therefore, the detailed machine transfer may have to be proved by future research.
  • UGT inhibitors can make many drugs with high first-pass effect and no oral administration can be administered orally, and also cause side effects of highly variable drugs. And its dosage range can be greatly reduced, and it can also reduce carcinogenic toxicants caused by UGT activation. Toxicity.
  • the present invention provides a UGT2B inhibitor which increases the bioavailability of a drug, which is a compound selected from the group consisting of the following in the form of a free base or a pharmaceutically acceptable salt: Prostol (capillarisin), isorhamnetin, ⁇ -naphthoflavone, a-naphthof lavone, hesperetin, terpineol, (+) - limonene ((+)- limonene), ⁇ -myrcene, swertiamarin, eriodictyol, cineole, apigenin, jaundice (baicalin), ursolic acid, isovitexin, lauryl alcohol, puerarin, trans-cirmamaldehyde, 3-acetic acid phenylpropionate (3-phenylpropyl acetate), isoliquritigenin, paeonif lorin, gallic acid, genistein
  • ethyl myri state ethyl myri state, umbelliferone, PEG (Polyethylene glycol) 400, PEG 2000, PEG 4000, Tween 20, Tween 60, Tween 80, BRIJ* 58, BRIjT 76 , Pluronic3 F68, Pluronic" F127, and combinations of these.
  • PEG Polyethylene glycol
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the aforementioned UGT2B inhibitor and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to the present invention can reduce the enzyme activity of UGT2B to supply a bioavailability for increasing a drug such as a morphine analgesic.
  • the present invention provides a UGT2B promoter which promotes a liver detoxification function of an individual, the promoter being selected from the group consisting of the following in the form of a free base or a pharmaceutically acceptable salt.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the aforementioned UGT2B accelerator and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to the present invention can promote the enzyme activity of UGT2B to supply a clearance rate for promoting a drug.
  • Figure 1 shows the effect of quercetin on the concentration of nalbumin in blood at different times after oral administration of nalbuphine in SD rats.
  • Figure 2 shows the effect of quercetin on the concentration of nalbufone in the blood at different times after intravenous administration of nalbuphine in SD rats.
  • Figure 3 shows changes in the concentration of nalbuphine in the blood of SD rats at different times in the experimental group of oral and intravenous nalbuphine in the two groups and in the experimental group of oral nalbuphine and chrome ketone. .
  • a first aspect of the invention provides a UGT2B inhibitor which is a compound selected from the group consisting of: a free base or a pharmaceutically acceptable salt: capillarisin, different Isorhamnetin, ⁇ -naphthoflavone, ct-naphthoflavone, hesperetin, terpineol, (+)-limonene ((+) -limonene), ⁇ -myrcene, swertiamarin, eriodictyol, cineole, apigenin, baicalin, bear Ursolic acid, isovitexin, lauryl alcohol puerarin, trans- cinnamaldehyde, 3-phenylpropyl acetate, Isoliquritigenin, paeonif lorin, gallic acid, genistein, glycyrrhizin, protocatechuic acid, ethyl citrate Myristate), umbelliferone (umb)
  • the UGT2B inhibitor is a compound selected from the group consisting of: a free base or a pharmaceutically acceptable salt: capillarisin, Isorhamnetin, ⁇ -naphthoflavone, ⁇ -naphthoflavone, hesperetin, terpineol, (+)-limonene ((+) - limonene), ⁇ -myrcene, swertiamarin, sage (eriodictyol), and a combination of these.
  • the UGT2B inhibitor is capillarisin.
  • the UGT2B inhibitor according to the present invention has been tested to increase the bioavailability of a drug. Therefore, the present invention also contemplates the use of the UGT2B inhibitor for the preparation of a pharmaceutical composition, particularly for morphine analgesics. drug.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the present invention provides a UGT2B promoter which is a compound selected from the group consisting of: a free base or a pharmaceutically acceptable salt; (nordihydroguaiaretic acid), wogonin, trans-cinnaraic acid, baicalein, quercetin, daidzein, oleanolic Acid), homoorientin, hesperetin, narigin, neohesperidin, (+)-epicatechin ((+) - epicatechin), hesperidin (hesperidin), liquiritin, eriodictyol, fortononetin, quercitrin, genkwanin, kaempferol, isoquercitrin ), (+)-catechin ((+)-catechin), naringenin, daidzin, (-)-epicatechin ((-)_ epicatechin), luteolin- 7-glucoside (luteolin-7
  • the UGT2B promoter is a compound selected from the group consisting of: a free base or a pharmaceutically acceptable salt: nordihydroguaiaretic acid ), wogonin, trans- cinnamic aci d, baicalein, quercetin, daidzein, oleanolic acid , homoorientin, hesperetin, narigin, neohesperidin, (+)-epicatechin ((+)-epicatechin), hesperidin ( Hesperidin), liquiritin and eriodictyol, and a combination of these.
  • the UGT2B promoter is nordihydroguaiaretic acid 0
  • the UGT2B promoter according to the present invention has been tested to increase the clearance rate of a drug. Therefore, the present invention also contemplates the use of the UGT2B promoter in the preparation of a pharmaceutical composition.
  • the present invention also provides a pharmaceutical composition comprising:
  • a pharmaceutical composition according to the present invention wherein the UGT2B promoter is administered in combination with an effective amount of a medicament for treating liver diseases.
  • the liver disease includes, but is not limited to, viral hepatitis, chronic hepatitis, alcoholic liver cirrhosis, compensated cirrhosis, or hepatic failure.
  • UGT2B inhibitors or promoters suitable for use in the present invention are readily available to those skilled in the art, such as synthetic techniques known to synthetic chemists, or purchased directly from the pharmaceutical industry, and may utilize the art. Conventional purification separation methods are isolated and purified from natural sources to obtain such a compound.
  • the UGT2B inhibitor or accelerator used was purchased from Sigma Chemical Co., Nacalai Tesque (Kyoto, Japan) and IND0FINE Chemical Co., Inc. (Somerville, New Jersey).
  • the term "pharmaceutically effective amount” means that when a pharmaceutical composition is administered in an amount which requires treatment with the composition, it inhibits or promotes UGT2B activity.
  • the pharmaceutically effective amount will vary depending on various factors including, for example, the type of disorder, the weight, age, physical condition and response of the individual to be treated, the route of administration of the drug, and the like. This therapeutically effective amount can be determined by those skilled in the art.
  • the term "pharmaceutically acceptable” means that the salt of the compound used as an inhibitor or promoter of UGT2B must be compatible with the other components of the composition and not deleterious.
  • the composition is administered to one body.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered to a body in a pharmaceutically effective amount, it may be administered alone or in combination with a drug such as a morphine-like analgesic agent.
  • the morphine analgesic comprises (-)-morphine ((-)-morphine), naloxone, nalorphine, hydroxydihydromorphone. (oxymorphone) hydromorphone, dihydromorphine, codeine, naltrexone, naltrindole, nalbuphine, and bupneufrafen (buprenorphine).
  • the morphine analgesic is nalbuphine.
  • composition according to the present invention can be produced into a form suitable for parenteral (e.g., intravenous) or enteral (e.g., oral) administration using techniques well known to those skilled in the art.
  • parenteral e.g., intravenous
  • enteral e.g., oral
  • the pharmaceutical composition of the present invention can be manufactured in a form suitable for injection, and the pharmaceutical composition can comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and for use in A sterile powder that is reconstituted into a sterile injectable solution or dispersion.
  • a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion Suitable for aqueous and non-aqueous loading
  • the agent, diluent, solvent or carrier include water, ethanol, propylene glycol, polyethylene glycol, glycerin and the like, and injectable organic esters such as ethyl oleate.
  • the pharmaceutical composition according to the present invention is manufactured in a form suitable for oral administration, and the oral dosage form includes a solid dosage form (such as a capsule, a tablet, a powder and a granule), and a liquid dosage form (such as a milk syrup).
  • a solid dosage form such as a capsule, a tablet, a powder and a granule
  • a liquid dosage form such as a milk syrup.
  • the pharmaceutical composition of the present invention and other drugs may be in different administration forms, for example, one may be delivered via a tablet, and the other may be administered by injection or orally in a syrup.
  • the pharmaceutical composition of the present invention can be administered simultaneously with other drugs, or continuously in any order, for example, in the case of a tablet, can be simultaneously present in a tablet. They may be present separately in separate lozenges and may be administered sequentially or in any order, all combinations, methods of delivery and order of administration may be contemplated by those skilled in the art.
  • the dosage and the number of administrations of the pharmaceutical composition according to the present invention vary depending on the following factors: the severity of the disease to be treated, the route of administration, and the body weight, age, physical condition and reaction of the individual to be treated .
  • the dose of each dose of the pharmaceutical composition according to the present invention can generally be estimated to be UGT2B inhibitor or accelerator/Kg body weight.
  • the dose range is 0. 01 mg I Kg body weight to 20 mg I Kg
  • the body weight is in the form of a single dose or divided into several doses and can be administered parenterally or orally.
  • the present invention employs 27 kinds of traditional Chinese medicines and 10 kinds of excipients as UGT2B inhibitors, wherein the traditional Chinese medicines are all commercially available pure compounds, which are purchased from Sigma Chemical Co., respectively. Nacalai Tesque (Kyoto, Japan) and IND0FINE Chemical Co., Inc. (Somerville, New Jersey). The types, names, sources of crude drugs, and chemical formulas of these Chinese medicines are shown in Table 1 below. These Chinese medicines were each formulated with ethanol to a concentration of 1, 10, and 100 ⁇ M for subsequent experiments.
  • the excipients are also commercially available pure compounds, namely PEG (Polyethylene glycol) 400, PEG 2000, PEG 4000, Tween 20, Tween 60, Tween 80, BRi 58, BR 76, Pluronic "F68, Pluronic” F127.
  • the excipients were separately formulated in water at a concentration of 0.5%, 5%, 50% by weight, w/v for subsequent experiments.
  • BRIJ is a registered trade name of ICI Americas, Inc.
  • Pluronic is a registered trade name of BASF Corporation
  • microsomes were prepared according to the following steps:
  • the removed supernatant is subjected to ultracentrifugation (L8-60M, Beckman, USA) at 105,000 X g for 60 minutes, and
  • microsomes Prior to use, the microsomes were thawed and BRIJT35 (5 ⁇ l/ ⁇ 1) was added at a volume ratio of 8:1 (microsome: ⁇ ? ⁇ 35) (Fisher et al. 2000, Drug Metabolism & Disposition- 28 (5): 560- 6).
  • BRIJT 35 solution 30% W/V BRIJ is the registered trademark name of ICI Americas, Inc.
  • the sample was subjected to the following steps to determine the protein content - i.
  • the 0.1 ml of the microsomes was diluted to 0.25 ml of 5 ml (50 volumes), from which 0.2 ml was taken and placed in a covered In the test tube (three repetitions); in addition, 0.2 ml of NaCl was used instead of the microsomes as a blank control group for this experiment.
  • Iii Add 0.1 ml of fol in reagent (SIGMA, 690-A) to each tube, mix immediately, rest at room temperature for 30 minutes, and measure the absorbance at 550 nm for 30 minutes. Density, and a protein based on the protein-bovine albumin concentration-absorbance value was used to calculate the protein content of the microsomes tested.
  • SIGMA fol in reagent
  • the mobile phase consists of 15% sodium acetate buffer (5 mM/L, pH 3) and 85% ACN at a flow rate of 1.0 mL per minute.
  • Fluorescence detector RF-551 , Shimadzu, Kyoto, Japan
  • the excitation light wavelength is 210 nm
  • the emission light wavelength is 345 nm
  • the ultraviolet light detector SPD-10A, Shimadzu, Kyoto, Japan uses a wavelength of 210 nm.
  • the nalbuphine was formulated to a concentration of 0.5, 1, 2.5, 5, 10, 15, 18, 20 raM. Formulated in water in a standard solution, such as with an inhibitor, diluted with alcohol because of the problem of formulating the inhibitor in alcohol.
  • Yinchen ketone has the best inhibitory effect on the metabolism of nalbuphine in liver microsomes, which can reach an inhibition rate of 111. 077 ( ⁇ 21. 807)%.
  • Other Chinese medicines including isorhamnetin, ⁇ _naphthoflavone, alpha-naphthoflavone, hesperetin, rosinol, (+)-limonene, beta-geranene, sauerkraut and ergomycin, can also achieve an inhibition rate of at least about 30%.
  • PEG 4000 has the best inhibitory effect on the metabolism of nalbuphine in liver microsomes, which can achieve an inhibition rate of 108.222 ( ⁇ 3.356)%; while other excipients, depending on the concentration, the optimal inhibition effect can reach at least about 60. % inhibition rate.
  • the results of the above experiments are shown in Table 6.
  • the positive dihydroxyleptic acid has the best promoting effect on the metabolism of nalbuphine in liver microsomes, which can reach -188.09 ( ⁇ 16.566)% inhibition rate, while other traditional Chinese medicines, including wogonin, trans Trans-cinnamic acid , baicalein
  • (eriodictyol) can also achieve at least about 30% promotion rate.
  • the animal source was the experimental male Sprague-Dawley strain, which was mainly made up of healthy rats weighing between 500-600 g and purchased from the National Laboratory Animal Breeding and Research Center (Taiwan). After the hook is hooked, the animals are given a one-week acclimation period and are kept at a fixed temperature (25 ⁇ 1 °C), humidity, and photoperiod (12 hours of light per day). Fasting for about 12-16 hours before the experiment.
  • the experimental method is to evaluate the drug absorption by oral administration.
  • nalbuphine The standard solution of nalbuphine is formulated in water and the inhibitor is formulated in alcohol.
  • LP. intraperitoneal injection
  • Iii Oral administration of 6 rats of the UGT 2B inhibitor, cytochrome (4 mg/Kg body weight) and nalbuphine (100 mg/kg body weight), as an experimental group, and the other six rats Only the dose of nalbuphine (100 mg/kg body weight) was administered as a blank control group.
  • 0.3 mL of blood samples were taken from PE-50 cannula at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration, and centrifuged at 10,000 rpm. The concentration of nalbuphine in plasma was analyzed with a 0.1 mL blood paddle.
  • ECD electrochemical chemical Detector
  • ESA electrochemical chemical Detector
  • the nalbufine drug dissolved in CAN was formulated into a concentration of 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 3000 ng/mL.
  • the time to reach the highest concentration in the blood (Tmax) was 25 ⁇ 5 min, and the highest concentration in the blood (Cmax) was 2582. 3 ⁇ 906. 6 ng/ml, and 4 mg/Kg of ketone ketone. .
  • Tmax time to reach the highest concentration in the blood
  • Cmax concentration in the blood
  • the control group and the experimental group were administered separately after At 0. 25 hours, the concentration of nalbuphine in the plasma of the experimental group was significantly higher than that of the control group by 32.68 times. With the increase of time, the difference of the concentration of nalbuphine decreased gradually.
  • V/F* (mL/kg) 2919123 ⁇ 863250 377412 ⁇ 170431
  • Fig. 2 shows the effect of the ketone ketone on the concentration of nalbuphine in the blood at different times after intravenous injection of nalbuphine.
  • the difference of the concentration of nalbuphine was gradually increased with the increase of time, and at 180 minutes, the plasma of the experimental group was in the middle of the cloth.
  • the concentration of the morphine was significantly higher than that of the control group by 2.37 times.
  • Figure 3 shows the changes in the concentration of nalbuphine in the blood of SD rats at different times in the two groups of the control group and the oral nalbuphine and chrome ketone ketone in the oral and intravenous nalbuphine. .
  • Oral absorption is mainly affected by the following three factors: gastrointestinal absorption, first-pass effect and other parts of metabolism, while intravenous injection is mainly affected by metabolism other than the first-pass effect, so as can be seen from Figure 3, oral administration of inhibitors Compared with the control group that only intravenously injects the drug, the oral absorption can be significantly improved in the presence of the inhibitor, and the absolute bioavailability is increased from 5% to 108%, and it can be seen that the AUC values of the two groups are very high. Similarly, this represents the effect of adding an inhibitor to promote oral absorption of nalbuphine.
  • the safe, effective and reversible UGT inhibitor provided by the invention can make many drugs with high first-pass effect and no oral administration can be administered orally, and also the side effects of highly variable drugs and The dosage range can be greatly reduced, and the toxicity of carcinogenic toxicants caused by UGT activation can also be reduced.
  • the present invention provides a safe, effective and reversible UGT promoter that increases the metabolic clearance rate of the drug to increase liver detoxification.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un inhibiteur de l’UGT2B qui peut augmenter la biodisponibilité des médicaments. L’inhibiteur de l’UGT2B est choisi parmi la capillarisine, l’isorhamnétine ou la β-naphtoflavone, etc., ou leurs combinaisons, sous la forme de base libre ou des sels pharmaceutiquement acceptables. La présente invention concerne également un promoteur de l’UGT2B qui peut favoriser la fonction individuelle d’élimination des toxines du foie. Le promoteur de l’UGT2B est choisi parmi l’acide nordihydroguaïarétique, la wogonine, l’acide trans-cinnamique, etc., ou leurs combinaisons, sous la forme de base libre ou des sels pharmaceutiquement acceptables.
PCT/CN2005/002167 2005-01-05 2005-12-13 Inhibiteur ou promoteur de l’uridinediphosphate-glucuronosyltransferase2b (ugt2b) WO2006072203A1 (fr)

Priority Applications (2)

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CA2593140A CA2593140C (fr) 2005-01-05 2005-12-13 Inhibiteur ou promoteur de l'uridinediphosphate-glucuronosyltransferase2b (ugt2b)
JP2007549784A JP5133064B2 (ja) 2005-01-05 2005-12-13 ウリジン２リン酸（ｕｄｐ）−グルクロン酸転移酵素２ｂ（ｕｇｔ２ｂ）の抑制剤及び促進剤

Applications Claiming Priority (2)

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US11/028,615 2005-01-05
US11/028,615 US20060040875A1 (en) 2004-01-08 2005-01-05 Inhibitors and enhancers of uridine diphosphate-glucuronosyltransferase 2B (UGT2B)

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CN (1) CN100571696C (fr)
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EP2664919A1 (fr) * 2012-05-15 2013-11-20 Jean Hilaire Saurat Une méthode pour identifier les ligands du récepteur AhR possédant une activité sebosuppressive thérapeutique
CN103143021A (zh) * 2013-03-21 2013-06-12 中国药科大学 PPARα-UGT通路抑制剂在治疗炎性肠疾病中的应用
BR112015025684A2 (pt) * 2013-04-08 2017-07-18 Indivior Uk Ltd método para proporcionar um ou mais opióide(s) a um indivíduo, forma de dosagem, método para tratar ou prevenir dor e método para tratar ou prevenir dependência ou vício
WO2016026139A1 (fr) * 2014-08-22 2016-02-25 财团法人国防教育研究基金会 Médicament pour le traitement de la stéatose hépatique non alcoolique et son utilisation
CN106191017B (zh) * 2015-05-25 2021-12-07 中国医学科学院药物研究所 一种来源于虎眼万年青的尿苷-5’-二磷酸芹菜糖/木糖合成酶，其核苷酸序列及应用
CN104876951B (zh) * 2015-05-26 2017-05-03 西安交通大学 一种葛根素吗啡的制备方法
CN104940190A (zh) * 2015-07-13 2015-09-30 江苏天晟药业有限公司 葛根素在制备镇痛药物中的应用
CN106008483A (zh) * 2016-06-08 2016-10-12 沈阳药科大学 异牡荆素的制备和用途
CN109512829A (zh) * 2017-09-19 2019-03-26 复旦大学 木犀草素7-o-葡萄糖苷在制备抗乙肝病毒药物中的应用
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JP2008526788A (ja) 2008-07-24
CN100571696C (zh) 2009-12-23
CA2593140A1 (fr) 2006-07-13
JP5133064B2 (ja) 2013-01-30
JP2011190267A (ja) 2011-09-29
CA2593140C (fr) 2013-08-13
CN1820743A (zh) 2006-08-23

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