JP2002220345A - Remedial agent for fatty liver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine for preventing and/or treating fatty liver that can prevent or cure fat accumulation in liver, decrease blood lipid, and can be used for a patient to whom a MTP inhibitor is administered, and also to provide a medicine for treating hyperlipidemia. SOLUTION: This invention relates to a medicine for preventing and/or treating fatty liver containing a PPARα activator as an active ingredient for a patient to whom a MTP inhibitor is administered, and also a medicine for treating hyperlipidemia containing a MTP inhibitor and PPARα activator as its active ingredients.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive and / or therapeutic agent for fatty liver and a therapeutic agent for hyperlipidemia.
More specifically, a prophylactic and / or therapeutic agent for fatty liver capable of preventing or treating fat accumulation in the liver and lowering blood lipids, and capable of treating hyperlipidemia, The present invention relates to a therapeutic agent for hyperlipidemia capable of suppressing the accumulation of lipids in the blood.

[0002]

2. Description of the Related Art In recent years, with the increase in obesity, the number of patients suffering from hyperlipidemia has been increasing. Drugs for such hyperlipidemia include microsomal triglyceride transport protein (microsomal triglyceride) in order to lower blood lipid (cholesterol, triglyceride, etc.) concentration.
glyceride transfer proteini
n) Inhibitors (hereinafter referred to as MTP inhibitors) are applied.

[0003] However, although the above-mentioned MTP inhibitor exerts a blood lipid lowering action, it may cause fat accumulation in the liver (fatty liver).

[0004] Therefore, without causing fatty liver,
There is a demand for the development of a drug capable of obtaining sufficient preventive and therapeutic effects.

[0005]

DISCLOSURE OF THE INVENTION The present invention relates to a method for activating PPARα, which is used for a patient to whom an MTP inhibitor is administered, which can prevent or treat fat accumulation in the liver and reduce blood lipids. An object of the present invention is to provide a preventive and / or therapeutic agent for fatty liver, which contains an agent as an active ingredient. Another object of the present invention is to provide a therapeutic agent for hyperlipidemia, which can treat hyperlipidemia and contains an MTP inhibitor and a PPARα activator as active ingredients.

[0006]

That is, the present invention provides:
[1] MTP (microsomal triglyceride transport protein; microsomal triglyceride)
PPARα (Peroxisome proliferator-activated receptor α; Peroxisome pr) used for a patient to whom a detransfer protein inhibitor is administered
oscillator-activated receive
ptor α) An agent for preventing and / or treating fatty liver, comprising an activator as an active ingredient, [2] MT
P inhibitor is BMS-201038, BAY13-99
52, CP-1047, R 103757 and WM
A prophylactic and / or therapeutic agent according to the above [1], which is a compound selected from the group consisting of -1159, [3] P
PARα activator is fenofibrate (Fenof)
ibrate), WY-14643, bezafibrate (Bezafibrate), clofibrate (Cl
offibrate), clinofibrate (Clino)
fibrate), 8 (S) -HETE, a prophylactic and / or therapeutic agent according to the above [1] or [2], which is a compound selected from the group consisting of ciprofibrate and gemfibrozil. [4] the prophylactic and / or therapeutic agent according to any of [1] to [3] above, wherein the PPARα activator is clinofibrate; [5] fatty liver is caused as a side effect of the MTP inhibitor The preventive and / or therapeutic agent according to any one of the above [1] to [4], which is a fatty liver; [6] an MTP inhibitor and PPARα
A hyperlipidemia therapeutic agent comprising an activator as an active ingredient, [7] an MTP inhibitor, BMS-201038,
BAY13-9952, CP-1047, R103
The therapeutic agent for hyperlipidemia according to the above [6], which is a compound selected from the group consisting of 757 and WM-1159.
[8] PPARα activator is fenofibrate,
Hyperlipidemia according to the above [6] or [7], which is a compound selected from the group consisting of WY-14643, bezafibrate, clofibrate, clinofibrate, 8 (S) -HETE, ciprofibrate and gemfibrozil. Therapeutic agents, and

[9] The therapeutic agent for hyperlipidemia according to any of [6] to [8], wherein the PPARα activator is clinofibrate.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have studied a quinazoline derivative which is an MTP inhibitor which is conventionally known to lower blood lipids but cause fat accumulation in the liver in animals and humans; By administering a fibrate, unexpectedly, suppressing fat accumulation in the liver,
And it is based on the surprising finding that blood lipids can be reduced.

That is, the prevention and / or prevention of fatty liver according to the present invention.
Alternatively, the therapeutic agent (fatty liver ameliorating agent) is a microsomal triglyceride transport protein [MTP (microsom
altilyceride transfer p
PTA used in patients receiving inhibitors
Ra (Peroxisome proliferato)
One major feature is that r-activated receptor α) activator is contained as an active ingredient. Since the prophylactic and / or therapeutic agent of the present invention has the above-mentioned active ingredient, it can suppress fat accumulation in the liver (onset of fatty liver), which occurs as a side effect in a patient administered with an MTP inhibitor, and lower blood lipids. It can exhibit the excellent property that it can be made.

[0009] Fatty liver is a state in which lipids, mainly triglycerides (hereinafter sometimes referred to as TG), and other triglycerides (TGs) are excessively accumulated in the liver. A state in which vacuoles are observed. Fatty liver is thought to develop when a disorder occurs in any of the processes of triglyceride synthesis and VLDL (very low density lipoprotein) synthesis and secretion in the liver.

As MTP inhibitors, BMS20103
8, BMS212122, BMS197636, BMS
200150, BMS192951, GR32871
3, CP-1047, WN-1159, BAY-13
-9952, R-103757, JTT-722, or N-benzocycloamide derivatives described in WO2000-05201 pamphlet, WO99
3-piperidyl described in -31085 pamphlet-
4-oxoquinazoline derivatives, WO 98-541
An ApoB secretion inhibitor described in pamphlet No. 35, an aminomethyl-substituted cyclic amine described in JP-A-11-35555, and the like, specifically, BMS-201
038, BAY13-9952, CP-1047, R
103757, WM-1159, JTT-722, G
R-328713 and the like. Among them, from the viewpoint of the effect, the following formulas (1) to (5):

[0011]

Embedded image

[0012]

Embedded image

[0013]

Embedded image

[0014]

Embedded image

[0015]

Embedded image

A compound represented by each of the following: BMS-2
01038, BAY13-9952, CP-1044
7, R 103757 and WM-1159 are preferred. The MTP inhibitor may be a pharmacologically acceptable salt as long as it can exert an MTP inhibitory action.
Examples of the pharmacologically acceptable salt include alkali metal salts such as sodium salt, potassium salt and lithium salt.

The PPARα activator used in the present invention may be any compound that enhances the β-oxidation system and lowers serum triglyceride. As described in the Examples below, a reporter gene evaluation of PPARα activating action is performed. Depending on the system (using the luciferase gene), selection can be made by examining the activity of the reporter gene when the compound is not added and when the compound is added.

The PPARα activator used in the present invention includes fibrate compounds, PPARα and PP
Agonists of ARγ and the like, specifically, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, fibrate-based compounds such as clinofibrate, for example,
And agonists of PPARα and PPARγ such as MCC-555 and KRP-297. Further, the PPARα activator may be a pharmacologically acceptable salt as long as the compound exerts a PPARα activation effect. Examples of the pharmacologically acceptable salt include alkali metal salts such as sodium salt, potassium salt and lithium salt.

The content of the PPARα activator in the prophylactic and / or therapeutic agent of the present invention can be appropriately set depending on the age, weight, disease state, etc. of the patient, and is about 10 to about 6000 mg / day for an adult per day. Days, preferably about 100 to about 1500 mg / day.

The pharmacological actions of the prophylactic and / or therapeutic agents of the present invention include, for example, (1) determining the PPARα activating action by a PPARα activating action evaluation system; (2)
The evaluation can be performed by, for example, determining a change in blood lipid concentration in a model animal for evaluation, or determining the accumulation of lipid in the liver.

(1) Evaluation system for PPARα activating action The activity of PPARα can be evaluated by the expression of a reporter gene using a cell line capable of examining the activation of PPARα by the expression of a reporter gene. For example, as described in the Examples, COS-1 cells contain GAL4-Luc [derived from plasmid pGL3-basic; having firefly luciferase, consensus GAL4 binding sequence, rabbit β-globin promoter], hPPARaLBD / pM.
[Having a human PPARαLBD and GAL4 binding region], pRL-CMW and pBluescript are introduced, and the resulting transduced cells are cultured with a preventive and / or therapeutic agent, and luciferase activity is measured. be able to.

(2) Evaluation of Changes in Blood Lipid Concentration and Evaluation of Lipid Accumulation in the Liver in Model Animals for Evaluation As animal models for evaluation, for example, animal models capable of reproducing hyperlipidemia, specifically Uses a sucrose-loaded animal model or the like. The animal used as the model animal includes a rat, a mouse, and the like. The sucrose-loaded animal model, particularly the sucrose-loaded rat model, is, for example, a male, 5 week-old Sprague-Da.
A wley rat [Crj: CD (SD)] can be obtained by loading under high sucrose diet and free feeding conditions for about 2 weeks.The sucrose-loaded rat model used for evaluation is preferably a serum triglyceride amount. Are desirably used in groups without variation.
In addition, a normolipidemic animal model used as a control, particularly a normolipidemic rat model is a male, 6-week-old Sprague-
It can be obtained by breeding Dawley rats [Crj: CD (SD), Charles River Japan] under a normal diet (CE-2) free-feeding condition for one week. More specifically, the pharmacological evaluation is performed by administering the prophylactic and / or therapeutic agent once a day at the set dose in the light period (8:00 to 2).
0:00) In the latter half, gavage was administered to each of the sucrose-loaded rat model and normolipidemic rat model,
After a certain number of days after the start of administration (for example, the first half of the light period on the fourth and seventh days), blood is collected from the orbital venous plexus, serum parameters are measured, and the liver is collected on the last day of the administration (for example, the seventh day). Extracting and measuring lipids in the liver by extracting lipids,
Can be performed. Here, at the time of addition compared to when no compound is added, a compound that reduces the concentration of blood lipids and suppresses or reduces lipid accumulation in the liver,
It is within the scope of the present invention.

The form of administration of the prophylactic and / or therapeutic agent of the present invention is determined according to the form of the preparation, the age, sex and other conditions of the patient, the degree of the disease, etc., and may be any of oral administration and parenteral administration. . Oral administration is preferred from the viewpoint of convenience in patients.

For oral administration, the prophylactic and / or therapeutic agents of the present invention can be used, for example, as unit dosage forms of powders, granules, tablets, pills, capsules, solutions and syrups.

For parenteral administration, the prophylactic and / or therapeutic agents of the present invention can be used as unit dosage forms such as injections and suppositories. The injection may be administered intravenously, alone or as a mixture with usual adjuvants such as glucose and amino acids, and may be administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. Suppositories are
It can be administered rectally.

For subcutaneous injection, intramuscular injection, local injection and intraperitoneal administration, the prophylactic and / or therapeutic agent of the present invention is used
It can be used as a form dissolved or suspended in an aqueous carrier (such as conventional water for injection) or a non-aqueous carrier (such as conventional oily solvent or hydrophilic solvent).

Further, the prophylactic and / or therapeutic agent of the present invention can be administered as a sustained-release preparation using a biocompatible material such as collagen.

For intravenous administration, the prophylactic and / or therapeutic agents of the present invention can be used as a solution dissolved or suspended in a pharmacologically acceptable carrier, preferably an aqueous carrier. As the aqueous carrier, for example, water, buffered water, physiological saline, and the like can be used. The aqueous solution thus prepared can be packaged as it is or lyophilized, and the lyophilized preparation can be used by dissolving it in a sterile aqueous solution before administration.

The prophylactic and / or therapeutic agent of the present invention may further contain a pharmacologically acceptable auxiliary. Examples of the adjuvant include an excipient, a buffer, a tonicity adjusting agent, a wetting agent, a binder, a filler, a stabilizer, a flavoring agent, and the like. More specifically, the prevention and / or
Or therapeutic agents, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, simple syrup, gelatin, sodium carboxymethylcellulose, gum arabic, sodium alginate, glycerin, It may contain D-mannitol and the like.

For example, the prophylactic and / or therapeutic agent of the present invention is provided as a tablet or capsule for oral administration, or as a unit dosage for administration of the above-mentioned dose.
Such a unit dose can be produced by adding an auxiliary agent such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a colorant, a flavoring agent, a wetting agent, and the like to the active ingredient. Can be. Tablets can be coated, for example, with conventional coating agents, for example, fillers such as cellulose, mannitol, lactose; disintegrants such as starch derivatives, polyvinylpolypyrrolidone; lubricants such as magnesium stearate; It can be manufactured by mixing, filling, or tableting using a wetting agent such as sodium lauryl sulfate.

When the prophylactic and / or therapeutic agent of the present invention is used as a liquid preparation for oral administration, such a liquid preparation may be, for example, an aqueous or oily suspension, solution, emulsion, syrup, etc. Sterilization, distilled water, etc.)
Alternatively, it is provided as a dry preparation which can be redissolved in a suitable medium. Such liquid preparations may contain usual additives such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, and a precipitation inhibitor such as aluminum stearate gel;
Emulsifiers such as lecithin, sorbitan monooleate and gum arabic; oily or non-aqueous vehicles such as olive oil and ethyl alcohol; preservatives such as methyl, ethyl or propyl esters of p-hydroxybenzoic acid; sorbic acid; coloring agents; You may mix a flavoring agent etc.

In the prophylactic and / or therapeutic agent of the present invention, a material for drug delivery may be appropriately used.

Further, by using an MTP inhibitor and a PPARα activator as active ingredients, the lipid concentration in blood can be reduced and the accumulation of lipid in the liver can be suppressed. Therefore, a drug containing such an active ingredient is useful as a therapeutic agent for hyperlipidemia. Such a therapeutic agent for hyperlipidemia is also included in the scope of the present invention.

The MTP inhibitor used in the present invention may be any compound having triglyceride lowering activity. As described in the evaluation system for MTP inhibitory action in the Examples described later, the activity of such a compound is determined by the artificial transmembrane triglyceride transport activity and the ApoB secretion inhibitory activity [for example, J. Am. Lip. Res. , 37, 1498
(1996)].

In the present invention, MTP inhibitors include:
The IC _{50 of the} artificial transmembrane triglyceride transport activity is several nM to
It is several μM, preferably 1 nM to 2 μM, and the IC _{50 of} HepG2 for inhibiting ApoB secretion is several nM to several μM, preferably 1 nM to 5 μM.

As such MTP inhibitors, the same compounds as described above (BMS-201038, BAY13-995)
2, CP-1047, R 103757, WM-11
59, pharmacologically acceptable salts thereof and the like).

MTP in the therapeutic agent for hyperlipidemia of the present invention
The content of the inhibitor can be appropriately set depending on the age, body weight, disease state and the like of the patient, and is preferably about 0.01 mg to about 100 mg / kg, more preferably about 0.1 mg to 1 kg / kg of adult body weight. Desirably, the dosage will be about 75 mg / kg.

As the PPARα activator used in the present invention, the same compounds as described above (fenofibrate, genfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate, pharmacologically acceptable salts thereof and the like) can be used. No.

PPA in the therapeutic agent for hyperlipidemia of the present invention
The content of the Rα activator can be appropriately set depending on the patient's age, body weight, disease state, etc., and is about 10 to 10 per adult per day.
It is desirably set to about 6000 mg / day, preferably about 100 to about 1500 mg / day.

The ratio of the MTP inhibitor to the PPARα activator in the therapeutic agent for hyperlipidemia of the present invention [MTP
Inhibitor / PPARα activator (molar ratio)] can be appropriately selected according to the disease of the patient. For example, an abundance ratio of 1 or less can be selected.

The administration form and dosage form of the therapeutic agent for hyperlipidemia of the present invention can be appropriately set depending on the age, weight, disease state, etc. of the patient. For example, the prevention and / or treatment of the fatty liver described above The same as the agent may be mentioned.

The pharmacological action of the therapeutic agent for hyperlipidemia of the present invention can be evaluated, for example, by the above-mentioned (1) system for evaluating PPARα activation and (3) the system for evaluating MTP inhibition. Determining the action; (2) determining the change in blood lipid concentration in the model animal for evaluation, determining the accumulation of lipid in the liver, and the like. For the evaluation methods (1) and (2), the description of the pharmacological evaluation of the preventive and / or therapeutic agent for fatty liver is referred to. Examples of the evaluation system of the above (3) include the following evaluation systems.

(3) MTP Inhibition Evaluation System Using a Triton-induced hyperglyceridemia (hyperlipidemia) animal model, a prophylactic and / or therapeutic agent was administered to an animal that had been fasted for an appropriate period of time. Triton is administered intravenously, blood is collected over time, serum triglyceride is measured, and the index is to decrease the triglyceride level when administered compared to before administration and / or non-administration.

The Triton-induced hyperglyceridemic model refers to a model animal in which Triton is intravenously administered to suppress the metabolism of triglyceride and thereby induce hypertriglyceridemia. Such model animals are described, for example, in Ishikawa
J. et al. Lipid Res. , 20,254-264
(1979).

[0045]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1 MTP activity inhibitory action and PP
Evaluation of ARα activating action (1) Evaluation of MTP activity inhibitory action VLDL secretion inhibitory action based on MTP activity inhibitory action
Evaluation was performed using a Triton-induced hypertriglyceridemia model rat. With respect to the model rats, see [Ishikawa et al. Lipid Res.
20, 254-264, (1979)]. Specifically, it is as follows.

Male, 5-week-old Sprague-Dawl
ey rats (Crj: CD (SD), manufactured by Charles River Japan) were preliminarily reared for one week. During the breeding period, the rats were allowed to freely eat a CE-2 solid sample (manufactured by CLEA Japan).

Next, regarding the rats after the preliminary rearing, 1
Fasted for more than 8 hours, then MTP as test compound
Inhibitors (BMS-201038, BAY13-995
2, CP-1047, R 103757 and WM-
1159) is orally administered. At an appropriate time (for example, one hour after administration), 300 mg / kg of Triton WR-1339 (manufactured by Nacalai Tesque) is administered to each rat via the tail vein, and blood is collected from the orbital venous plexus over time. As a control, vehicle alone is administered.

Thereafter, the collected blood is centrifuged to separate serum. For the obtained serum, the serum triglyceride level is measured using a measurement kit (trade name: Triglyceride E-test, manufactured by Wako Pure Chemical Industries, Ltd.).

As a result, since the serum triglyceride level at the time of administration of the test compound was lower than that of the control, the test compound exhibited a VTP based on the MTP activity inhibitory action.
It turns out that it has an LDL secretion inhibitory action.

(2) Evaluation of PPARα activating action COS-1 cells were placed in a 24-well plate at 1.25 × 1
0 ⁴ cells / 500 [mu] l / well (= ~3 × 10 ⁵ cells /
Plate), and the next day, the gene was introduced by the lipofection method. The gene transfer was performed using TransIT (registered trademark) -LT1 (PANVERA) and according to the attached protocol of the manufacturer. Serum-free RPMI as medium
1640 medium was used.

The amount of plasmid added during the gene transfer treatment in the evaluation system was GAL4-Luc (derived from plasmid pGL3-basic; firefly luciferase, consensus GAL4 binding sequence, rabbit β-globin promoter; 0.05 μg) per well, hPPARaLBD
/ PM [human PPARαLBD, having GAL4 binding region; 0.005 μg], pRL-CMW (0.002
5 μg), pBluescript (0.4425 μg)
g).

After 4 hours from the gene transfer treatment, the cells were washed,
It was replaced with DMEM (without phenol red) containing 5% by weight activated carbon-treated bovine serum-10-8 M insulin. Further, test compounds: clinofibrate, WY-146
43 (manufactured by Cayman), Bezafibrate (SIG
MA), fenofibrate (manufactured by SIGMA, used after decomposing into carboxylic acid type) or DMSO solution in which clofibrate (manufactured by ALDRICH) is dissolved, or ethanol solution in which 8 (S) -HETE (manufactured by Cayman) is dissolved Was added to the cells, and the cells were cultured for 24 hours.

Hereinafter, Dual-Luciferase
Following treatment with 100 μl of cell lysate, luciferase activity was measured according to the standard protocol of Reporter Assay System (promega).
Firefly luciferase activity / Renilla luciferase activity was calculated, and the magnification relative to the value of test compound untreated cells was calculated.

As a positive control for evaluating the PPARα activating effect, various fibrate compounds and 8 (S) -HETE, a lipid considered to be one of the ligands in vivo, are used as positive controls.
Was used to examine a system for evaluating PPARα activation. The PPARα activating effect of the compound was calculated by setting the increase in luciferase activity at the time of treatment with 30 μM of WY-14643 used as a positive control as 100, and quantifying the increase in activity at the time of treatment with each compound. Clinofibrate, WY
-14643 (manufactured by Cayman), bezafibrate (manufactured by SIGMA), fenofibrate (SIGM)
A and Table 2 show the evaluation results of the PPARα activation of clofibrate (ALDRICH) in the same manner.

[0056]

[Table 1]

[0057]

[Table 2]

From the results in Tables 1 and 2, it can be seen that the PPARα activating effect can be evaluated by such an evaluation system.

Example 2 Male, 5-week-old Sprague-Dawley rat [Crj: CD (SD), manufactured by Charles River Japan Co., Ltd.]
High sucrose diet for about 2 weeks [HIGH SUCROSE
AIN-76A DIET, PURINA MILL
S, INC. (Handling by Japan SLC)] Preload was performed under free feeding conditions. The obtained rat was used as a sucrose-loaded rat model.

The sucrose-loaded rat models were divided into groups of 6 mice each so that the amount of serum triglyceride did not vary. BMS-201038, BAY13-9952 or clinofibrate was administered by oral gavage once daily in the latter half of the light period (8:00 to 20:00) at the doses shown in Tables 5 and 6. The solvent was 0.5% by weight methylcellulose, and the solution was administered at 5 ml / kg.

Blood was collected from the orbital venous plexus on the fourth and seventh days of the light period after the start of administration, and serum parameters were measured. On the last day, the liver was excised on the seventh day, lipids were extracted, and lipids in the liver were measured.

On the other hand, male, 6-week-old Sprague-D
Awley rats [Crj: CD (SD), manufactured by Charles River Japan Co., Ltd.] were bred for 1 week under a normal diet (CE-2) free-feeding condition. The obtained rat was used as a normolipidemic rat model.

BMS-201038 and BAY13-
For both 9952, one of the efficacy onset doses in the efficacy evaluation model
It was set from the 0-fold dose. The solvent was 0.5% by weight methylcellulose and administered at 5 ml / kg.

The normolipidemic rat model was divided into groups of 4 animals each with no variation in serum triglycerides, and BMS-201038 or BAY13-9952 was administered once a day under the same age at the time of administration. Times, light period (8:00)
２０20: 00) Gavage was administered in the latter half. 4 after start of administration
Blood was collected from the orbital venous plexus in the first half of the light period on days 7 and 7, and serum parameters were measured. On the last day, the liver was excised on the seventh day, lipids were extracted, and lipids in the liver were measured.

Tables 3 and 4 show the relationship between the serum lipid lowering effect and hepatic fat accumulation in a normolipidemic rat model. Furthermore, Table 5 and Table 6 similarly show the effect of combination with a fibrate drug in a sucrose-loaded rat model. Tables 3 and 5 show serum triglyceride and cholesterol values for each group and the inhibition rate for the control group, and Tables 4 and 6 show hepatic triglyceride and cholesterol contents for each group and their fold ratio for the control group. And In the table, “vehicle alone” indicates a model administered with the vehicle alone, and such a model was used as a control group. The “TG inhibition rate” indicates the triglyceride inhibition rate, and the “TC inhibition rate” indicates the cholesterol inhibition rate.

[0066]

[Table 3]

[0067]

[Table 4]

[0068]

[Table 5]

[0069]

[Table 6]

As shown in Tables 3 and 4, in a normolipidemic rat model, when a drug whose dose was 10 times as effective as that in the sucrose-loaded rat model was used, the serum triglyceride amount was reduced, but the triglyceride level in the liver was reduced. It can be seen that accumulates.

On the other hand, as shown in Tables 5 and 6, the combined use with a fibrate-based drug which promotes β-oxidation in the liver and has a PPARα activating effect is more potent than that of the single administration. In addition to showing a lipid-lowering effect, liver fat accumulation is significantly reduced, and liver triglyceride is at a normal level. It was suggested that the directional effect of positively increasing the β-oxidation, such as the PPARα activating effect, was added.

In the normolipidemic rat model, which is a normal metabolic level, even though there is some difference from the 10-fold dose of the onset of efficacy in the sucrose-loaded rat model,
Both AY and BMS drugs also showed a clear tendency to accumulate, and it was considered that the discrepancy between the expression of hepatic fat accumulation and the effect of the drug was at least 10 times or less in rats. Although the hepatic fat content is lower than in the sucrose load model, the possibility of hepatic fat accumulation cannot be denied.

As described above, the combined use of an MTP inhibitor and a fibrate-based drug which is considered to have a β-oxidation-enhancing action based on PPARα-activating action shows a stronger serum lipid-lowering action and markedly reduces hepatic fat accumulation. Is shown to decrease.

[0074]

According to the preventive and / or therapeutic agent for fatty liver of the present invention, it is possible to prevent or treat fat accumulation in the liver and to reduce blood lipids. . In addition, according to the therapeutic agent for hyperlipidemia of the present invention, accumulation of fat in the liver (fatty liver onset)
While suppressing blood lipid concentration, thereby achieving an excellent effect of being able to treat hyperlipidemia.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/496 A61K 31/496 31/513 31/513 45/06 45/06 A61P 1/16 A61P 1/16 3 / 06 3/06 (72) Inventor Masafumi Tanaka 3-1-98 Kasuganaka, Konohana-ku, Osaka F-term (reference) in Sumitomo Pharmaceutical Co., Ltd.4C084 AA17 AA20 MA02 NA06 NA14 ZA751 ZA752 ZC331 ZC332 ZC751 4C086 AA01 AA02 BC21 BC42 BC60 CB05 GA02 GA07 GA12 MA01 MA02 MA04 MA09 NA06 NA07 NA14 ZA75 ZC33 ZC75 4C206 AA01 AA02 DA28 DB25 DB43 GA09 GA28 KA01 MA01 MA02 MA04 NA06 NA07 ZA75 ZC33 ZC75

Claims (9)

[Claims] Claims 1. An MTP (microsomal triglyceride transport protein; microsomal triglyc)
PPARα (Peroxisome proliferator-activated receptor α; Peroxisome) used for patients to which an eride transfer protein inhibitor is administered
proliferator-activated r
(ceptor α) An agent for preventing and / or treating fatty liver, comprising an activator as an active ingredient. 2. The method of claim 1, wherein the MTP inhibitor is BMS-20103.
8, BAY13-9952, CP-1047, R1
The preventive and / or therapeutic agent according to claim 1, which is a compound selected from the group consisting of 03757 and WM-1159. 3. The method of claim 1, wherein the PPARα activator is fenofibrate, WY-14643,
Bezafibrate, Clofibrate, Clinofibrate, 8 (S) -HET
E, Ciprofibrate
The prophylactic and / or therapeutic agent according to claim 1 or 2, which is a compound selected from the group consisting of and gemfibrozil. 4. The preventive and / or therapeutic agent according to claim 1, wherein the PPARα activator is clinofibrate. 5. The preventive and / or therapeutic agent according to claim 1, wherein the fatty liver is a fatty liver induced as a side effect of an MTP inhibitor. 6. A therapeutic agent for hyperlipidemia comprising an MTP inhibitor and a PPARα activator as active ingredients. 7. The method of claim 7, wherein the MTP inhibitor is BMS-20103.
8, BAY13-9952, CP-1047, R1
The therapeutic agent for hyperlipidemia according to claim 6, which is a compound selected from the group consisting of 03757 and WM-1159. 8. The method of claim 1, wherein the PPARα activator is fenofibrate, WY-14643,
Bezafibrate, Clofibrate, Clinofibrate, 8 (S) -HET
E, Ciprofibrate
The therapeutic agent for hyperlipidemia according to claim 6 or 7, which is a compound selected from the group consisting of gemfibrozil and gemfibrozil. 9. The therapeutic agent for hyperlipidemia according to claim 6, wherein the PPARα activator is clinofibrate.