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Identification
NameEnalapril
Accession NumberDB00584  (APRD00510)
Typesmall molecule
Groupsapproved
Description

Enalapril is a prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly metabolized in the liver to enalaprilat following oral administration. Enalaprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Enalapril may be used to treat essential or renovascular hypertension and symptomatic congestive heart failure.

Structure
Thumb
Synonyms
SynonymLanguageCode
EnalaprilFrench/German/SpanishINN
EnalaprilumLatinINN
Salts
Name/CAS Structure Properties
Enalapril Maleate
Thumb Not applicable DBSALT001036
Brand names
NameCompany
AcetecAlphapharm
AcetensilGrünenthal
AlaprenRanbaxy
AmotacMass Pharma
AmpraceMerck Sharp & Dohme
DilvasCipla
DiotensilMintlab
DrepatilFada
EnaceAbbott
EnaHexalSandoz
EnalEast West
EnalapotenDel Bel
EnprilWockhardt
FeliberalSilanes
GadoprilGador (Argentina)
GliotenBago
KinfilNova Argentia (Argentina)
VasotecMerck Frosst (Canada)
Vasotec IVSandoz (Canada)
Brand mixtures
Brand NameIngredients
EnzideEnalapril and Hydrochlorothiazide
Lexxelenalapril maleate + felodipine
Vasereticenalapril maleate + hydrochlorothiazide
Categories
CAS number75847-73-3
WeightAverage: 376.4467
Monoisotopic: 376.199822016
Chemical FormulaC20H28N2O5
InChI KeyInChIKey=GBXSMTUPTTWBMN-XIRDDKMYSA-N
InChI
InChI=1S/C20H28N2O5/c1-3-27-20(26)16(12-11-15-8-5-4-6-9-15)21-14(2)18(23)22-13-7-10-17(22)19(24)25/h4-6,8-9,14,16-17,21H,3,7,10-13H2,1-2H3,(H,24,25)/t14-,16-,17-/m0/s1
IUPAC Name
(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid
SMILES
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsN-acyl-alpha Amino Acids; Alpha Amino Acid Esters; Alpha Amino Acid Amides; Phenylpropylamines; Pyrrolidine Carboxylic Acids; Fatty Acid Esters; Dicarboxylic Acids and Derivatives; Tertiary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acid Esters; Carboxylic Acids; Dialkylamines; Polyamines; Enolates; Ethers
Substituentsn-acyl-alpha amino acid or derivative; alpha-amino acid ester; n-acyl-alpha-amino acid; alpha-amino acid amide; alpha-amino acid or derivative; phenylpropylamine; pyrrolidine carboxylic acid or derivative; pyrrolidine carboxylic acid; fatty acid ester; dicarboxylic acid derivative; benzene; pyrrolidine; tertiary carboxylic acid amide; tertiary amine; carboxamide group; carboxylic acid ester; polyamine; secondary amine; carboxylic acid; ether; enolate; secondary aliphatic amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
Pharmacology
IndicationFor the treatment of essential or renovascular hypertension and symptomatic congestive heart failure. It may be used alone or in combination with thiazide diuretics.
PharmacodynamicsEnalapril is a prodrug that is rapidly metabolized by liver esterases to enalaprilat following oral administration. Enalapril itself has little pharmacologic activity. Enalaprilat lowers blood pressure by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of enalaprilat by causing increased vasodilation and decreased blood pressure.
Mechanism of actionThere are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Enalaprilat, the principle active metabolite of enalapril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Enalapril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Enalaprilat's affinity for ACE is approximately 200,000 times greater than that of ATI and 300-1000 times greater than that enalapril.
Absorption55-75%, absorption is unaffected by food; enalaprilat (clinically administered IV) is poorly absorbed, 3-12%, due to its high polarity.
Volume of distributionNot Available
Protein binding50-60% of enalaprilat is bound to plasma proteins
Metabolism

~ 60% of absorbed dose is extensively hydrolyzed to enalaprilat, primarily by liver esterases

SubstrateEnzymesProduct
Enalapril
    EnalaprilatDetails
    Route of eliminationExcretion of enalapril is primarily renal.
    Half life< 2 hours for unchanged enalapril in health individuals, may be increased in those with congestive heart failure (3.4 and 5.8 hours for single 5- and 10-mg doses, respectively). The average terminal half life of enalaprilat is 35-38 hours. The effective half life following multiple doses is 11-14 hours.
    ClearanceNot Available
    ToxicityOverdosage may result in marked hypotension and stupor. Most common adverse effects include hypotension, headache, dizziness and fatigue.
    Affected organisms
    • Humans and other mammals
    Pathways
    PathwayCategorySMPDB ID
    Enalapril Action PathwayDrug actionSMP00148
    Enalapril Metabolism PathwayDrug metabolismSMP00593
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.7428
    Blood Brain Barrier - 0.9659
    Caco-2 permeable - 0.8956
    P-glycoprotein substrate Substrate 0.7691
    P-glycoprotein inhibitor I Non-inhibitor 0.6681
    P-glycoprotein inhibitor II Non-inhibitor 0.5136
    Renal organic cation transporter Non-inhibitor 0.8442
    CYP450 2C9 substrate Non-substrate 0.8632
    CYP450 2D6 substrate Non-substrate 0.9116
    CYP450 3A4 substrate Non-substrate 0.5696
    CYP450 1A2 substrate Non-inhibitor 0.9125
    CYP450 2C9 substrate Non-inhibitor 0.9154
    CYP450 2D6 substrate Non-inhibitor 0.9231
    CYP450 2C19 substrate Non-inhibitor 0.9025
    CYP450 3A4 substrate Non-inhibitor 0.8309
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6825
    Ames test Non AMES toxic 0.9383
    Carcinogenicity Non-carcinogens 0.9216
    Biodegradation Not ready biodegradable 0.8686
    Rat acute toxicity 1.8269 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9719
    hERG inhibition (predictor II) Non-inhibitor 0.7456
    Pharmacoeconomics
    Manufacturers
    • Apotex inc
    • Apothecon inc div bristol myers squibb
    • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
    • Krka dd novo mesto
    • Lek pharmaceuticals d d
    • Mylan pharmaceuticals inc
    • Ranbaxy laboratories ltd
    • Sandoz inc
    • Taro pharmaceutical industries ltd
    • Teva pharmaceuticals usa inc
    • Watson laboratories inc
    • Wockhardt americas inc
    • Biovail laboratories international srl
    • Bedford laboratories div ben venue laboratories inc
    • Hikma farmaceutica (portugal) sa
    • Hospira inc
    • Teva parenteral medicines inc
    Packagers
    Dosage forms
    FormRouteStrength
    Injection, solutionIntravenous1.25 mg/ml
    TabletOral10 mg
    TabletOral2.5 mg
    TabletOral20 mg
    TabletOral5 mg
    Prices
    Unit descriptionCostUnit
    Enalapril maleate powder9.18USDg
    Enalaprilat 1.25 mg/ml vial3.6USDml
    Vasotec 20 mg tablet3.36USDtablet
    Vaseretic 10-25 mg tablet3.15USDtablet
    Vasotec 10 mg tablet2.63USDtablet
    Vasotec 5 mg tablet2.08USDtablet
    Vasotec 2.5 mg tablet1.65USDtablet
    Enalapril maleate 20 mg tablet1.56USDtablet
    Vaseretic 5-12.5 mg tablet1.49USDtablet
    Vasotec 20 mg Tablet1.34USDtablet
    Vasotec 10 mg Tablet1.11USDtablet
    Enalapril maleate 10 mg tablet1.09USDtablet
    Enalapril maleate 5 mg tablet1.03USDtablet
    Vasotec 5 mg Tablet0.92USDtablet
    Enalapril maleate 2.5 mg tablet0.82USDtablet
    Vasotec 2.5 mg Tablet0.78USDtablet
    Apo-Enalapril 20 mg Tablet0.75USDtablet
    Co Enalapril 20 mg Tablet0.75USDtablet
    Mylan-Enalapril 20 mg Tablet0.75USDtablet
    Novo-Enalapril 20 mg Tablet0.75USDtablet
    Pms-Enalapril 20 mg Tablet0.75USDtablet
    Ratio-Enalapril 20 mg Tablet0.75USDtablet
    Sandoz Enalapril 20 mg Tablet0.75USDtablet
    Taro-Enalapril 20 mg Tablet0.75USDtablet
    Apo-Enalapril 10 mg Tablet0.62USDtablet
    Co Enalapril 10 mg Tablet0.62USDtablet
    Mylan-Enalapril 10 mg Tablet0.62USDtablet
    Novo-Enalapril 10 mg Tablet0.62USDtablet
    Pms-Enalapril 10 mg Tablet0.62USDtablet
    Ratio-Enalapril 10 mg Tablet0.62USDtablet
    Sandoz Enalapril 10 mg Tablet0.62USDtablet
    Taro-Enalapril 10 mg Tablet0.62USDtablet
    Apo-Enalapril 5 mg Tablet0.52USDtablet
    Co Enalapril 5 mg Tablet0.52USDtablet
    Mylan-Enalapril 5 mg Tablet0.52USDtablet
    Novo-Enalapril 5 mg Tablet0.52USDtablet
    Pms-Enalapril 5 mg Tablet0.52USDtablet
    Ratio-Enalapril 5 mg Tablet0.52USDtablet
    Sandoz Enalapril 5 mg Tablet0.52USDtablet
    Taro-Enalapril 5 mg Tablet0.52USDtablet
    Apo-Enalapril 2.5 mg Tablet0.44USDtablet
    Co Enalapril 2.5 mg Tablet0.44USDtablet
    Mylan-Enalapril 2.5 mg Tablet0.44USDtablet
    Novo-Enalapril 2.5 mg Tablet0.44USDtablet
    Pms-Enalapril 2.5 mg Tablet0.44USDtablet
    Ratio-Enalapril 2.5 mg Tablet0.44USDtablet
    Sandoz Enalapril 2.5 mg Tablet0.44USDtablet
    Taro-Enalapril 2.5 mg Tablet0.44USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    PatentsNot Available
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point143-144.5 °CNot Available
    water solubility1.64E+004 mg/L (at 25 °C)MCFARLAND,JW ET AL. (2001)
    logP0.07HANSCH,C ET AL. (1995)
    Caco2 permeability-5.64ADME Research, USCD
    pKa2.97 (the carboxyl group) and 5.35 (the amine group) at 25°CNot Available
    Predicted Properties
    PropertyValueSource
    water solubility2.13e-01 g/lALOGPS
    logP0.19ALOGPS
    logP0.59ChemAxon
    logS-3.2ALOGPS
    pKa (strongest acidic)3.67ChemAxon
    pKa (strongest basic)5.2ChemAxon
    physiological charge-1ChemAxon
    hydrogen acceptor count5ChemAxon
    hydrogen donor count2ChemAxon
    polar surface area95.94ChemAxon
    rotatable bond count10ChemAxon
    refractivity99.57ChemAxon
    polarizability40.41ChemAxon
    number of rings2ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    K. S. Keshava Murthy, Andrew Burchat, Gamini Weeratunga, “Sodium enalapril complex and the use thereof to make sodium enalapril.” U.S. Patent US5637730, issued February, 1983.

    US5637730
    General Reference
    1. D.P. Ip and G.S. Brenner, in K. Florey (Editor), Analytical Profiles of Drug Substances, Vol. 16, Aca- demic Press, London, 1987, pp. 207-243.
    External Links
    ResourceLink
    KEGG CompoundC06977
    ChEBI4784
    ChEMBLCHEMBL578
    Therapeutic Targets DatabaseDAP001374
    PharmGKBPA449456
    HETEAL
    Drug Product Database2019906
    RxListhttp://www.rxlist.com/cgi/generic/enalap.htm
    Drugs.comhttp://www.drugs.com/enalapril.html
    PDRhealthhttp://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=Vas1477.html&contentName=Vasotec&contentId=6
    WikipediaEnalapril
    ATC CodesC09AA02
    AHFS Codes
    • 24:32.04
    PDB Entries
    FDA labelshow(939 KB)
    MSDSNot Available
    Interactions
    Drug Interactions
    Drug
    AmilorideIncreased risk of hyperkalemia
    Azilsartan medoxomilPharmacodynamic synergism: dual blockade of renin-angiotensin system. Increases risks of hypotension, hyperkalemia, renal impairment.
    DrospirenoneIncreased risk of hyperkalemia
    IcatibantIcatibant may attenuate the antihypertensive effect of ACE inhibitors by pharmacodynamic antagonism. Monitor concomitant therapy closely.
    Insulin LisproConcomitant therapy with ACE inhibitors may increase the blood-glucose-lowering effect of insulin lispro and thus the chance of hypoglycemia should be monitored closely.
    LithiumThe ACE inhibitor increases serum levels of lithium
    PotassiumIncreased risk of hyperkalemia
    RifampicinRifampin, a strong CYP3A4 inducer, may increase the metabolism of enalapril. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of enalapril if rifampin is initiated, discontinued or dose changed.
    SpironolactoneIncreased risk of hyperkalemia
    TizanidineTizanidine increases the risk of hypotension with the ACE inhibitor
    TobramycinIncreased risk of nephrotoxicity
    TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
    TriamtereneIncreased risk of hyperkalemia
    Food Interactions
    • Enalapril decreases the excretion of potassium. Salt substitutes containing potassium increase the risk of hyperkalemia.
    • Herbs that may attenuate the antihypertensive effect of enalapril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
    • High salt intake may attenuate the antihypertensive effect of enalapril.
    • Take without regard to meals.

    1. Angiotensin-converting enzyme

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Angiotensin-converting enzyme P12821 Details

    References:

    1. Andujar-Sanchez M, Jara-Perez V, Camara-Artigas A: Thermodynamic determination of the binding constants of angiotensin-converting enzyme inhibitors by a displacement method. FEBS Lett. 2007 Jul 24;581(18):3449-54. Epub 2007 Jun 27. Pubmed
    2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
    3. Liu YH, Liu LY, Wu JX, Chen SX, Sun YX: Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. J Cardiovasc Pharmacol. 2006 Jan;47(1):82-8. Pubmed
    4. Natesh R, Schwager SL, Evans HR, Sturrock ED, Acharya KR: Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry. 2004 Jul 13;43(27):8718-24. Pubmed

    1. Cytochrome P450 3A4

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 3A4 P08684 Details

    References:

    1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

    1. Multidrug resistance protein 1

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Multidrug resistance protein 1 P08183 Details

    References:

    1. Takara K, Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K: Interaction of digoxin with antihypertensive drugs via MDR1. Life Sci. 2002 Feb 15;70(13):1491-500. Pubmed

    2. Solute carrier family 15 member 1

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate inhibitor

    Components

    Name UniProt ID Details
    Solute carrier family 15 member 1 P46059 Details

    References:

    1. Han H, de Vrueh RL, Rhie JK, Covitz KM, Smith PL, Lee CP, Oh DM, Sadee W, Amidon GL: 5’-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res. 1998 Aug;15(8):1154-9. Pubmed
    2. Han HK, Rhie JK, Oh DM, Saito G, Hsu CP, Stewart BH, Amidon GL: CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs. J Pharm Sci. 1999 Mar;88(3):347-50. Pubmed
    3. Temple CS, Boyd CA: Proton-coupled oligopeptide transport by rat renal cortical brush border membrane vesicles: a functional analysis using ACE inhibitors to determine the isoform of the transporter. Biochim Biophys Acta. 1998 Aug 14;1373(1):277-81. Pubmed
    4. Tsuji A: Transporter-mediated Drug Interactions. Drug Metab Pharmacokinet. 2002;17(4):253-74. Pubmed

    3. Solute carrier family 22 member 6

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Solute carrier family 22 member 6 Q4U2R8 Details

    References:

    1. Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, You G: Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem. 1999 Jan 15;274(3):1519-24. Pubmed

    4. Solute carrier family 22 member 8

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Solute carrier family 22 member 8 Q8TCC7 Details

    References:

    1. Kobayashi Y, Ohshiro N, Tsuchiya A, Kohyama N, Ohbayashi M, Yamamoto T: Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOat3): further substrate specificity of mOat3. Drug Metab Dispos. 2004 May;32(5):479-83. Pubmed

    5. Solute carrier family 22 member 7

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Solute carrier family 22 member 7 Q9Y694 Details

    References:

    1. Kobayashi Y, Ohshiro N, Shibusawa A, Sasaki T, Tokuyama S, Sekine T, Endou H, Yamamoto T: Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice. Mol Pharmacol. 2002 Jul;62(1):7-14. Pubmed
    2. Sekine T, Cha SH, Tsuda M, Apiwattanakul N, Nakajima N, Kanai Y, Endou H: Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett. 1998 Jun 12;429(2):179-82. Pubmed

    6. Solute carrier organic anion transporter family member 1A2

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Solute carrier organic anion transporter family member 1A2 P46721 Details

    References:

    1. Abu-Zahra TN, Wolkoff AW, Kim RB, Pang KS: Uptake of enalapril and expression of organic anion transporting polypeptide 1 in zonal, isolated rat hepatocytes. Drug Metab Dispos. 2000 Jul;28(7):801-6. Pubmed
    2. Pang KS, Wang PJ, Chung AY, Wolkoff AW: The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein. Hepatology. 1998 Nov;28(5):1341-6. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11