KR100377430B1 - Pharmaceutical composition with abnormal drug metabolism containing sulfur-containing amino acid and changed drug dynamics - Google Patents

Abstract

The present invention relates to the use of sulfur-containing amino acids or derivatives thereof to correct abnormal drug metabolism caused by protein deficiency, tuberculosis, cancer, digestive system diseases, AIDS, fasting / hunger, diabetes mellitus, and to change the reverse hydrodynamics The present invention relates to a pharmaceutical composition containing an amino acid or a derivative thereof as an active ingredient and a conventional adjuvant, and correcting abnormal drug metabolism caused by administering the composition of the present invention to a human or an animal, and correcting modified bad kinetics. .

Description

Use for abnormal expression of pharmacokinase and modified pharmacokinetics of sulfur-containing amino acids or derivatives thereof and pharmaceutical compositions containing the sulfur-containing amino acids or derivatives thereof as active ingredients

Many people in the world, especially in Africa and Asia, are malnourished, and malnutrition also occurs in many disease states, including tuberculosis, cancer, digestive system diseases, and AIDS. The deficiency of protein-calories in humans or animals has been shown to change the pharmacokinetics and pharmacodynamics of therapeutic agents (Kim and Lee, 1993, Kim et al., 1993). In the case of a protein deficiency diet, or a fasting, a change in the physiological state may significantly change the expression of major metabolic enzymes in the liver and other major organs, and these changes may change the pharmacodynamic indicators. Therefore, by administering a drug that normalizes or minimizes the expression and metabolism of drug metabolism in tissues, it may be possible to normalize molecular regulation and ultimately provide improved drug therapy to patients when metabolic normalization is achieved.

Studies related to the present invention have shown a pharmacodynamic change in animals chronically fed a low protein diet (Kim and Lee, 1993, Kim et al., 1993). These changes not only lead to increased drug toxicity, changes in drug intervals, and increased drug interactions, but can also increase oxidative stress and cell / tissue damage in tissues due to changes in enzyme expression (Daniel , 1993). In addition, it can be seen that toxic expression by the administered drug is significantly increased in fasting / hunger or similar pathological diabetes (Kim et al., 1998). Induction or inhibition of detoxification enzymes causes pharmacodynamic changes and affects the pharmacodynamics of the drug used clinically. Therefore, these changes should be taken into account when determining the dose of the drug and should be reflected when administering the drug to patients clinically.

Therefore, an object of the present invention is to change the manifestation of various cytochrome P450 in major organs including hepatic tissue where drug metabolism occurs (eg, induction, inhibition), microsomal epoxide hydrolase (mEH), a secondary detoxification enzyme. And use of sulfur-containing amino acids or derivatives thereof to correct expression changes of detoxification enzymes such as glutathione S-transferase (GST) and pharmaceutical compositions containing the sulfur-containing amino acids or derivatives thereof as an active ingredient. To provide.

Another object of the present invention is to overcome the changes in metabolic enzyme expression in protein-caloric deficiency and starvation / fasting state to overcome tissue damage, oxidative stress caused by metabolic enzyme expression, and to normalize drug metabolic disturbance. The present invention provides a use of a sulfur-containing amino acid or a derivative thereof to correct kinetic changes, and a pharmaceutical composition containing the sulfur-containing amino acid or a derivative thereof as an active ingredient.

Another object of the present invention is to administer the sulfur-containing amino acids or derivatives thereof to overcome the changes in the expression of metabolic enzymes in protein-caloric deficiency and starvation / fasting state, thereby preventing tissue damage and oxidative stress caused by changes in metabolic enzyme expression. To overcome and to normalize pharmacokinetic disturbances by normalizing drug metabolism disturbances, and to provide a pharmaceutical composition containing the sulfur-containing amino acids or derivatives thereof as an active ingredient.

1 shows the expression of cytochrome P450 in liver tissue.

Figure 2 shows the effect of cysteine, cystine or methionine supplementation on the changes in cytochrome P450 expression by low protein diet.

3 shows mEH protein expression.

Figure 4 shows the increase in mEH and rGSTA2 mRNA expression by low protein diet.

5 shows mEH mRNA expression when 4-methylthiazole is administered to fasted animals.

Figure 6 shows the effect of cysteine or methionine on histotoxicity by 4-methylthiazole.

Figure 7 shows the plasma concentration of Azosemide and its metabolite M1.

The present invention is a drug that can be caused by protein supply restriction or protein metabolism disturbance such as malnutrition that occurs in people or animals in tuberculosis, tuberculosis, cancer, digestive diseases and AIDS patients by administering sulfur-containing amino acids or derivatives thereof. It is to provide a use for normalizing abnormal expression of metabolic enzymes, normalizing abnormal drug metabolism caused by changes in intracellular redox level, and a pharmaceutical composition containing the sulfur-containing amino acid or derivative thereof as an active ingredient. Experimental expression of cytochrome P450, mEH and GST changes in liver tissues when rats were fed low-protein (5% protein-containing diet) for 4 weeks. When a low-protein diet is administered, protein synthesis is altered by sulfur-containing amino acids and their derivatives, which are associated with oxidative stress in the cells due to changes in detoxification enzyme expression in liver tissues caused by protein supply restriction. will be.

The present invention overcomes changes in the expression of drug metabolism enzymes in protein-caloric deficiency and starvation / fasting state, overcomes tissue damage, oxidative stress caused by metabolic enzyme expression changes, and normalizes drug metabolic disturbances. The present invention relates to the use of sulfur-containing amino acids or derivatives thereof and a pharmaceutical composition containing the compound as an active ingredient. In the present invention, the changes in the expression of drug metabolism enzymes caused by protein deficiency are mainly cysteine, cystine and methionine, cysteate, N-acetylcysteine, and homocysteine. (x) was observed to normalize by supplementing sulfur-containing amino acids such as homexcysteine and homocysteate and compounds of related structures. Induction of mEH and rGSTA2 in secondary conjugated drug metabolism, in particular, is mediated by intracellular gene antioxidant (ARE). Therefore, it was observed that the increase of intracellular oxidative stress due to protein supply ultimately altered the expression of mEH and that the metabolic enzyme disruption was normalized by the administration of sulfur-containing amino acids and the antioxidant vitamin C / E. Experimentally, the differential expression of cytochrome P450 and mEH genes and the metabolic enzyme expression in rats fed 5% protein were normalized by sulfur-containing drugs.

The expression of P450 1A2, 2C11, 2E1 and 3A1 / 2 in liver tissues was decreased when the low protein diet was administered, but P450 2B2 expression was increased. When supplemented with sulfur-containing amino acids such as cysteine, cystine or methionine or derivatives thereof, the altered cytochrome P450 expression was largely normalized. In contrast, mEH and rGSTA2 expressions were elevated in the animals with protein metabolism and mRNAs of these genes were significantly increased. For example, the mEH gene is transcriptionally activated by stimulation of reactive oxygen radicals produced by metabolizing compounds in vivo (Kim and Cho, 1996). In studies related to the present invention, the protein deficiency was found to significantly increase the mEH mRNA level. Therefore, it is assumed that protein supply restriction causes oxidative stress in hepatocytes. When administering the pharmaceutical composition of the present invention, changes in protein and mRNA expression were fully or partially restored to normal levels. Increased mRNA levels were restored to normal levels when supplemented with cysteine, cystine or methionine or its derivatives for one week in animals that received a diet lowered to 5% protein for 4 weeks. The increase in mEH protein and mRNA induction due to protein deficiency and the ability to normalize the expression of enzymes with sulfur-containing drugs supports the hypothesis that protein deficiency causes oxidative stress in liver tissue. Oxidative metabolism of drugs in hepatocytes can lead to depletion of GSH, which plays an important role in detoxification, and increase the susceptibility to tissue damage due to free radicals. Studies related to the present invention show that P450 and mEH expression changes are restored when supplemented with cysteine, cystine, methionine, as well as cystate, N-acetylcysteine, homocystate (hereinafter sulfur-containing amino acids) and vitamin C / E. Appeared to be. In conclusion, the expression and detoxification of the major cytochrome P450 phase II enzymes in animals treated with a protein-deficient diet are opposite to each other. Pharmacokinetic changes were also corrected.

In the present invention, it has also been found that the use of an antioxidant such as vitamin C or vitamin E in combination with sulfur-containing amino acids or derivatives thereof enhances the effect.

Sulfur-containing amino acids or derivatives thereof of the present invention are administered from 0.1 mg to 1000 mg / kg body weight per day.

In the present invention, it is also possible to enhance the effect by using at least one vitamin selected from vitamin C and vitamin E in normal doses.

In the present invention, excipients, adjuvants, solubilizers, antioxidants, stabilizers, preservatives and the like which are commonly used in medicine can be added and formulated.

Formulation Example 1

The above ingredients are mixed in a conventional manner and filled into capsules to prepare capsules.

Formulation Example 2

The above ingredients are filled into capsules according to a conventional method for preparing capsules to prepare capsules.

Example 3

The above components are mixed and compressed in a conventional manner to prepare tablets.

Example 4

Dissolving the above components in purified water, making the whole to 100ml and filling into a brown bottle to prepare a liquid.

Experimental Example 1

Expression Changes of Cytochrome P450 by Protein Supply Restriction

In the present invention, male Sprague-Dawley rats (180-220 g) were divided into two groups, and normal diet containing 23% casein and protein deficiency feed containing 5% casein were administered for 4 weeks. Feed ingredients are listed in Table 1.

TABLE 1

Composition of normal protein or low protein diet (per kg diet).

1 salt mixture (g / kg): Ca (calcium carbonate), 300; K (dipotassium phosphate), 322.5; Mg (magnesium sulfate), 102; P (monocalcium phosphate), 75; Na (sodium chloride), 167.5; Fe (ferric citrate), 27; I (potassium iodide), 0.8; Zn (zinc chloride), 0.25; Cu (copper sulfate), 0.3; Salt mixture consisting of Mn (manganese sulfate) 5.

2 fat soluble vitamin mixture: tocopherol acetate (Vit. E), 5 g; Menadiene (Vit. K), 200 mg; Corn oil, fat-soluble vitamin mixture consisting of 200 mg.

3 Vitamin A, D Blend: Vitamin A, 0.1 (850 I. U.); Vitamin D, 0.01 (85 I.U.).

4 water soluble vitamin mixture: choline chloride, 2000; Thiamine hydrochloride, 10; Riboflavin, 20; Nicotinic acid, 120; Pyridoxine, 10; Calcium pantothenate, 100; Biotin. 0.05; Folic acid, 44: inositol, 5000; A water-soluble vitamin mixture consisting of para-aminobenzoic acid, 100.

Liver tissues were excised from animals fed each feed, and the tissues were crushed with a waring blender and microsome fractions were isolated. The rats were fasted 16 hours before the rats were killed. After the liver tissue was cut, two-fold doses of 0.1 M Tris-KCl buffer (0.1 M Tris, 0.1 M KCl, 1 mM EDTA, pH 7.4) were added, and the tissues were pulverized using an Osterizer blender. The pulverized tissue was centrifuged at 8,000g for 30 minutes and 10,000g for 30 minutes with a high-speed centrifuge, and then the supernatant was taken and ultracentrifuged at 100,000g to obtain precipitated microsomes and the supernatant cytosol. Separated. Microsomes were redispersed in 50 mM Tris buffer (50 mM Tris, 20% glycerol, 1 mM EDTA, pH 7.4), and stored at −70 ° C. until dispensed. All manipulations were carried out at 4 ° C. or lower, and proteins were quantified by the Lowry method (1951).

Mighty Small II SE 250 electrophoresis device was used for electrophoresis with 7.5% microsomes and 12% gels according to Laemli method (1970).

Immunochemical assays were used to determine the amount of protein changed (Kim et al., 1996). After electrophoresis was transferred to nitrocellulose (NC) paper, the gel was stained with amido black to confirm the transition, and then simply washed with water and incubated at 37 ° C for 1 hour in 5% skim milk. Immunohistochemical analysis of mEH and GST was performed by diluting anti-rat P450 2E1, mEH and GST antibodies in phosphate buffered saline solution in a ratio of 1: 1000, sealing them in a plastic bag, sealing them, and shaking them overnight. After shaking for 1 hour, streptavidin-horseradish peroxidase was added for 1 hour for color development. However, before proceeding to the next step in all processes were washed three times with phosphate buffered saline tween solution, once with phosphate buffered saline solution. 9 ml of phosphate buffered saline solution, 3 ml of 4-chloro-1-naphthol and 150 μl of 30% hydrogen peroxide solution were added. When color began to appear, the mixture was immediately placed in distilled water to stop the reaction and dried. To carry out immunoblot of cytochrome P450, mouse monoclonal antibodies anti-rat P450 1A1 / 2, 2B1 / 2, 2E1, 2C11 and 3A1 / 2 antibodies were used, and goat anti mouse-IgG was used as a secondary antibody. Color development was performed with 5-bromo-4-chloro-3-indolephosphate and nitroblue tetrazolium.

Animals fed the feed containing 5% protein showed rapid growth inhibition after 4 weeks. The low protein diet group lost weight significantly compared to the normal animal group, a 23% protein diet group. This is shown in Table 2.

TABLE 2

Changes in body weight and feed intake of protein-deficient animals

Value = mean ± S.D. (n = 6).

Immunohistochemical analysis was performed by electrophoresis of microsomal proteins in liver tissue to observe the expression of P450 1A2, 2B1 / 2, 2C11, 2E1 and 3A1 / 2 after a diet containing 5% or 23% casein in rats for 4 weeks. Was carried out. The results are shown in FIG. Referring to Figure 1, the animals administered with a diet deficient in 5% protein for 4 weeks, P450 1A2 amount was reduced by 90% compared to the control group. P450 2C11 was also significantly inhibited by protein deficiency, whereas P450 2B2 expression was 8-fold higher in animals treated with low-protein feeds for 4 weeks, compared with 40% -50 in P450 2E1 and 3A1 / 2. It turned out that it was suppressed by%.

Experimental Example 2

Effects of Cysteine, Cystine, and Methionine Supplementation on Changes of Enzyme Expression by Protein Restriction

Liver cytochrome P450 expression did not change when 23% casein diet group (normal diet group) received cysteine, cystine or methionine twice daily (500 mg / kg per day) at a dose of 250 mg / kg. However, cysteine, cystine or methionine were administered orally for the last week at a dose of 500 mg / kg (250 mg / kg × 2, po). Cysteine was orally administered in aqueous solution, and cystine and methionine were suspended in 0.1% carboxymethyl cellulose solution. P450 expression occurred when animals were given a 5% protein-deficient diet for 4 weeks (protein deficiency) when cysteine, cystine or methionine were administered twice daily at 250 mg / kg for the last week of protein deficiency. Normally or partially normalized. When weekly supplementation of cysteine, cystine or methionine was given to animals that were fed a diet deficient in 5% protein for 4 weeks, P450 1A2 expression was inhibited by 60% and 20%, respectively, compared to the normal diet group. Compared with the 90% suppression result. However, cysteine, cystine or methionine did not normalize the altered P450 2B2 expression. P450 2C11 expression was significantly reduced in the protein deficient group and partially recovered by supplementation with cysteine, cystine or methionine. Animals that received diets depleted at 5% protein for 4 weeks had approximately 60% reduction in P450 2E1 expression and were fully normalized by cysteine supplementation. Reduced P450 3A1 / 2 expression was partially normalized by cysteine. Thus, cysteine, cystine or methionine supplementation improved most of the reduced P450 expression to steady state. Methionine recovered weaker but altered P450 expression than cysteine. This is shown in Figure 2 by immunochemical analysis. Other sulfur-containing drugs such as cystate, N-acetylcysteine, homocysteine, homocysteate and fat-soluble vitamins; Tocopherol acetate (Vit. E), menadione (Vit. K), corn oil and water soluble vitamins; This improvement has also been observed with choline chloride, thiamine hydrochloride, riboflavin, nicotinic acid, pyridoxine, calcium pantothenate, biotin, polyacid, inositol, para-aminobenzoic acid. Table 3 shows the effect of these citrate, N-acetylcysteine, homocysteine and homocysteine on the changes of P450 and mEH by protein metabolism. In addition, Table 4 shows the effects of vitamin C / E on the changes of P450 and mEH caused by protein metabolism.

Changes in the level of P450 in liver tissues were fully or partially normalized when the sulfur-containing drug was administered for a week at a dose of 0.1 mg / kg-1000 mg / kg per day to animals fed a low protein diet.

TABLE 3

Value = average of the control percentages

TABLE 4

Effects of Vitamin C / E Supply on Changes of P450 and mEH by Protein Metabolism

Value = mean ± S.D. Of control percent (n = 3).

Vitamin C / E was orally administered for 7 days at a dose of 200 mg / kg each day.

Experimental Example 3

Effect of mEH-induced Expression and Supplementation of Sulfur-Containing Pharmaceutical Compositions by Protein Restriction

Administration of rats with a 5% protein reduction induced an increase in mEH expression in liver tissues (approximately 3 fold). This marked rise in mEH gene expression suggests that a low protein diet may cause oxidative stress in hepatocytes. When cysteine was administered orally twice a day at a dose of 250 mg / kg once, the weight of mEH was completely normalized.

It was observed by Northern blot analysis whether the induction of mEH protein was accompanied by mEH mRNA expression (FIG. 4). Total RNA was isolated from liver tissue by Puissant and Houdebine (1970). The isolated total RNA was dissolved in a sample buffer buffer (50% formamide, 2.2M formaldehyde in 1x MOPS). RNA was denatured and loaded onto 1% agarose gel and electrophoresed using MOPS buffer as a buffer. After electrophoresis, fractionated RNA present in the gel was transferred to nitrocellulose (NC) paper for more than 12 hours using a capillary phenomenon, and the transferred NC paper was dried in a vacuum oven at 80 ° C. for 2 hours. The method of attaching isotopes to the cDNA sample used in the experiment was used a random prime labeling technique. DATP, dGTP, dTTP, [α- ³² P] dCTP, random prime buffer and Klenow fragment were added to the denatured 10ng mEH and rGSTA2 cDNA and reacted at 25 ° C for 1 hour. The reaction solution was loaded on a Sephadex 50 column and centrifuged to obtain a labeled sample. Hybridization consists of 50% deionized formamide, 5x Denhardt's solution (0.1% Ficoll, 0.1% polyvinylpyrrolidine, 0.1% bevine serum albumin), 0.5% SDS, 0.5mg / ml ssDNA, 5x SSPE (1xSSPE: 0.15M NaCl, 10nM NaH ₂ PO ₄ , 1mM Na ₂ EDTA, pH 7.4) in the hybridization buffer containing NC paper was prehybridized at 42 ℃ for 2 hours. The labeled sample was added and reacted at 42 ° C. for 18 hours, followed by washing twice at room temperature with 2 × SSC / 0.1% SDS and 0.1x SSC / 0.1% SDS for 15 minutes each, at 55 ° C with 0.1x SSC / 0.1% SDS. Wash for 1 hour. After hybridization, NC paper was exposed to Kodak X-Omat AR film at -70 ℃ and developed. The developed film was quantified using a micro computer imaging device.

MEH mRNA was increased by about 20-fold in liver tissues of animals fed the diet containing 5% low protein. Induced increased mEH mRNA levels returned to normal when the protein deficient animals were supplemented with cysteine, cystine or methionine for the last week. Methionine also restored a significantly increased mEH to normal when the same dose was administered over the same period, but its effect was weaker than that of cysteine or cystine. In addition, mEH induction was restored to normal state by the supply of cystate, N-acetylcysteine, homocysteine or homocysteine. Enzyme expression did not change when supplemented with amino acids containing sulfur in the normal diet. Thus, these sulfur-containing drugs have been shown to restore normal expression of disturbed metabolic enzymes. Induction of mEH in liver tissue due to protein deficiency was immunochemically analyzed. The 23% or 5% casein diet group was supplemented with cysteine, cystine or methionine to normalize protein deficiency-induced mEH expression. This is shown in FIG. 3.

Northern blotting was performed by separating total RNA from liver tissue of 23% or 5% casein diet animals. Each mRNA expression returned to normal when supplemented with cysteine, cystine or methionine during the last week of 4 weeks of 5% protein administration. This is shown in FIG. 4.

Experimental Example 4

Effect of Sulfur-Containing Pharmaceutical Compositions on Metabolic Disturbance by Fasting

In the fasting model, reactive oxygen radicals produced by metabolic activation by P450 increase mEH and rGSTA2 expression. In the fasting model, mEH and rGSTA2 mRNA levels were observed when cysteine was administered for 3 days when 4-methylthiazole, a hepatotoxic substance, was administered at a dose of 30 mg / kg. Sulfur-containing pharmaceutical composition inhibited the induction of mEH and rGSTA2 by 4-methylthiazole generated by fasting. Unlike normal animals, tissue damage was observed when 4-methylthiazole was administered in a fasted state induced by P450 2E1. On the other hand, when cysteine was administered to the fasted animals for 3 days, tissue damage by 4-methylthiazole was not observed. 4-methylthiazole-induced tissue damage in P450 2E1-induced animals such as acetone or isoniazid was also prevented by sulfur-containing drugs. Therefore, the sulfur-containing drug showed metabolic normalization because it controls excessive metabolism that may occur due to fasting or increased expression of metabolic enzymes by drugs.

After fasting for 16 hours or 72 hours, 30 mg / kg of 4-methylthiazole was administered and mEH mRNA expression was analyzed by Northern blotting. After 72 hours of fasting, mEHH mRNA levels induced by 4-methylthiazole were normalized by cysteine or methionine feed. This is shown in FIG. 5.

Liver tissue was fixed in 10% formalin and embedded in paraffin. The liver was cut to a thickness of 5 μm, made into slides, stained with hematoxylin and eosin, and observed at 100 or 450 magnification. Tissue necrosis induced by 4-methylthiazole was not observed when pretreated with cysteine or methionine. This is shown in FIG. 6. 6, A, B and C are as follows.

A. The liver tissue obtained after 24 hours after 4-methylthiazole was administered at a dose of 30 mg / kg to a 72-hour fasted animal was necrotic.

B. Liver obtained from rats treated with the same dose of 4-methylthiazole in the fasted animal group administered with cysteine for 3 days was not necrotic.

C. Hepatotoxicity was lost when 4-methylthiazole was administered to fasted rats treated with methionine for 3 days.

Experimental Example 5

In the present invention, male Sprague-Dawley rats (115-146 g) are divided into three groups, normal feed containing 23% casein (treatment I, n = 17), protein deficiency feed containing 5% casein (treatment II, n = 11) was administered for 4 weeks. Protein deficiency feed containing 5% casein was administered for 4 weeks and cysteine was administered twice a day (500 mg / kg per day) at a dose of 250 mg / kg for 1 week from the third week (treatment III, n = 11) . At the end of 4 weeks, azosemide, 10 mg / kg, was administered intravenous infusion for 1 minute each week, and pharmacokinetic parameters were measured by analyzing plasma and urine azosemide and its metabolites, M1. The plasma concentration-curve area (AUC) of Azosemide was significantly reduced by cysteine administration. This is because the metabolism of azosemide, which was reduced to protein deficiency, was restored to almost normal level. This is indicated by the increase in total body clearance (CL), renal clearance (CL _R ) and nonrenal clearance (CL _NR ) than protein deficiency and the increase of metabolite M1 urinary excretion (AUC _m1 ). The amount of azosemide excreted in urine (X _U , _{0-8 hr} ) was also lower than that of protein deficiency. This is shown in Figure 7 and Table 5. Figure 7 is the plasma concentration of Azosemide was measured at the above time after 1 minute intravenous administration of Azosemide at a dose of 10 mg / kg in the following animal model (rat).

The plasma concentrations of Azosemide in Table 5 were measured after intravenous administration of Azosemide at a dose of 10 mg / kg for 1 minute in the following animal model (rat).

Normal group (treatment I, n, 17); Protein caloric deficiency group (treatment II, n = 11): Protein caloric deficiency group supplemented with cysteine (treatment III, ○, n = 11).

TABLE 5

^a Treatment I was significantly different (p <0.05) from II and III

^b Treatment II was significantly different (p <0.05) from I and III

^c Treatment III was significantly different (p <0.05) from I and II

^d Treatment I was significantly different (p <0.05) from III

^e Treatment II was significantly different (p <0.05) from III

Drugs that may be caused by protein supply restriction or protein metabolism disturbances such as tuberculosis, cancer, gastrointestinal disease, and AIDS patients in tuberculosis, cancer, digestive system diseases and AIDS patients in humans or animals in malnutrition by administering the pharmaceutical composition of the present invention to humans or animals It can normalize the abnormal expression of metabolic enzymes and normalize the abnormal drug metabolism caused by the change of intracellular redox level.

In summary, the expression of cytochrome P450 and mEH in liver tissues was observed by administration of the pharmaceutical composition of the present invention, and the altered drug metabolic enzyme expression was normalized by the sulfur-containing pharmaceutical composition of the present invention. When diets lowered to 5% were administered to animals, expression of cytochrome P450 1A2, P450 3A1 / 2 and P450 2E1 enzymes was significantly inhibited, but P450 2B2 expression was increased. Rapid growth inhibition occurred in the animals fed the diet containing 5% protein, and the serum concentrations of the drug were increased in the animals fed the protein-deficient diet. The amount of P450 reduced in liver tissue was largely normalized by supplementation of the sulfur-containing pharmaceutical composition described in the present invention. Supplementation of cysteine, cystine or methionine did not restore body weight in the protein deficient group, but normalized most of the altered cytochrome P450 expression and pharmacokinetic changes. Similar effects were also observed with cysteate, N-acetylcysteine, homocysteine and homocysteate. In addition, sulfur-containing drugs have been shown to protect against tissue damage caused by metabolic and oxidative stress caused by fasting or organic solvent administration. However, these pharmaceutical compositions did not affect the metabolism of animals fed a normal diet, so they have a selective corrective action only in situations that cause metabolic abnormalities.

Altered P450 expression in liver tissues was fully or partially normalized when a low-protein diet was administered for one week at a dose of 0.1 mg / kg-1000 mg / kg of sulfur-containing medication to animals. Based on the present invention, claims are made for the use of cysteine, systein, methionine, cysteate, N-acetylcysteine, homocysteine, homocysteate, vitamin C / E as a corrective agent for drug metabolism. Among them, vitamin C and E indirectly reduce the required amount of cysteine by reducing the use of intracellular cysteine, so it can be used as a sulfur-containing drug and a combination drug as shown in the experimental example.

references

Claims (1)

It contains at least one sulfur-containing amino acid selected from cysteine, cystine, methionine, cystate, N-acetylcysteine, homocysteine and homocystate as an active ingredient, and a conventional pharmaceutically acceptable excipient, adjuvant, antioxidant, dissolution aid Cytochrome P450, Klutachi, caused by diseases involving protein deficiency and protein deficiency selected from tuberculosis, cancer, hunger and digestive system diseases, containing adjuvant selected in the art and formulated in conventional pharmaceutically acceptable methods A pharmaceutical composition containing sulfur-containing amino acids that correct for abnormal changes in drug metabolases selected from on S-transferase and microsomal epoxide hydrolase.