DT-Web

DB00968 - Methyldopa


Identification
Name Methyldopa
Accession Number DB00968 (APRD01106)
Type small molecule
Description An alpha-2 adrenergic agonist that has both central and peripheral nervous system effects. Its primary clinical use is as an antihypertensive agent. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 211.2145
Groups approved
Monoisotopic Weight 211.084457909
Pharmacology
Indication For use in the treatment of hypertension.
Mechanism of action Although the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa)--the precursor of norepinephrine--and of 5-hydroxytryptophan (5-HTP)--the precursor of serotonin--in the CNS and in most peripheral tissues.
Absorption Absorption from the gastrointestinal tract is variable but averages approximately 50%.
Protein binding Low (less than 20%).
Biotransformation Hepatic, extensively metabolized. The known urinary metabolites are: a-methyldopa mono-0-sulfate; 3-0-methyl-a-methyldopa; 3,4-dihydroxyphenylacetone; a-methyldopamine; 3-0-methyl-a-methyldopamine and their conjugates.
Route of elimination Methyldopa is extensively metabolized. The known urinary metabolites are: ?-methyldopa mono-O-sulfate; 3-0-methyl-?-methyldopa; 3,4-dihydroxyphenylacetone; ?-methyldopamine; 3-0-methyl-?-methyldopamine and their conjugates. Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.
Toxicity The oral LD50 of methyldopa is greater than 1.5 g/kg in both the mouse and the rat. Symptoms of overdose include bloating, constipation, diarrhea, dizziness, extreme drowsiness, gas, light-headedness, nausea, severely low blood pressure, slow heartbeat, vomiting, and weakness.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Carteolol Possible hypertensive crisis
Dobutamine Increased arterial pressure
Dopamine Increased arterial pressure
Entacapone Entacapone may increase the effect and toxicity of the sympathomimetic, methyldopa.
Ephedra Increased arterial pressure
Ephedrine Increased arterial pressure
Epinephrine Increased arterial pressure
Fenoterol Increased arterial pressure
Haloperidol Methyldopa increases haloperidol effect or risk of psychosis
Iron Iron decreases the absorption of dopa derivatives
Iron Dextran Iron decreases the absorption of dopa derivatives
Isoproterenol Increased arterial pressure
Levodopa Methyldopa increases the effect and toxicity of levodopa
Lithium Methyldopa may increase the adverse effects of lithium without affecting lithium serum levels. Monitor for signs and symptoms of lithium toxicity during concomitant therapy.
Mephentermine Increased arterial pressure
Metaraminol Increased arterial pressure
Methoxamine Increased arterial pressure
Nadolol Possible hypertensive crisis
Norepinephrine Increased arterial pressure
Orciprenaline Increased arterial pressure
Oxprenolol Possible hypertensive crisis
Penbutolol Possible hypertensive crisis
Phenylephrine Increased arterial pressure
Phenylpropanolamine Increased arterial pressure
Pindolol Possible hypertensive crisis
Pirbuterol Increased arterial pressure
Procaterol Increased arterial pressure
Propranolol Possible hypertensive crisis
Pseudoephedrine Increased arterial pressure
Salbutamol Increased arterial pressure
Sotalol Possible hypertensive crisis
Terbutaline Increased arterial pressure
Timolol Possible hypertensive crisis
Tranylcypromine The MAO inhibitor, Tranylcypromine, may increase the adverse effects of Methyldopa. Concomitant therapy is contraindicated.
Food Interactions
  • Take without regard to meals.
  • May take Vitamin D.
  • No iron, zinc or fluoride within 2 hours of taking this medication.
  • Avoid alcohol.
  • Avoid natural licorice.
  • Increase dietary intake of magnesium, folate, vitamin B6, B12, and/or consider taking a multivitamin.

Targets


Alpha-2A adrenergic receptor
Name Alpha-2A adrenergic receptor
Gene Name ADRA2A
Pharmacological action yes
Actions Not Available
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Sica DA: Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405. - Pubmed
  • Kawasaki H: [Centrally acting sympathetic inhibitors for therapy of patients with hypertension] Nippon Rinsho. 1997 Aug;55(8):2081-5. - Pubmed
  • Head GA: Central imidazoline- and alpha 2-receptors involved in the cardiovascular actions of centrally acting antihypertensive agents. Ann N Y Acad Sci. 1999 Jun 21;881:279-86. - Pubmed
  • van Zwieten PA: New central mediators as targets of centrally acting antihypertensive drugs. Clin Exp Hypertens. 1996 Apr-May;18(3-4):291-303. - Pubmed
  • van Zwieten PA: Development and trends in the drug treatment of essential hypertension. J Hypertens Suppl. 1992 Dec;10(7):S1-12. - Pubmed
  • Velliquette RA, Ernsberger P: Contrasting metabolic effects of antihypertensive agents. J Pharmacol Exp Ther. 2003 Dec;307(3):1104-11. Epub 2003 Oct 13. - Pubmed
DTHybrid score 0.2644

Enzymes


Catechol O-methyltransferase
Name Catechol O-methyltransferase
Gene Name COMT
Actions substrate
References
  • Alazizi A, Liu MY, Williams FE, Kurogi K, Sakakibara Y, Suiko M, Liu MC: Identification, characterization, and ontogenic study of a catechol O-methyltransferase from zebrafish. Aquat Toxicol. 2011 Mar;102(1-2):18-23. Epub 2010 Dec 29. - Pubmed
  • Ameyaw MM, Syvanen AC, Ulmanen I, Ofori-Adjei D, McLeod HL: Pharmacogenetics of catechol-O-methyltransferase: frequency of low activity allele in a Ghanaian population. Hum Mutat. 2000 Nov;16(5):445-6. - Pubmed
DTHybrid score 0.7912

Transporters


Oligopeptide transporter, small intestine isoform
Name Oligopeptide transporter, small intestine isoform
Gene Name SLC15A1
Actions inhibitor
References
  • 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
DTHybrid score 0.3012

Predictions


Id Partner name Gene Name Score
1974 Oligopeptide transporter, kidney isoform SLC15A2 0.1854
556 Alpha-1A adrenergic receptor ADRA1A 0.098
244 Angiotensin-converting enzyme ACE 0.0936
378 Alpha-2C adrenergic receptor ADRA2C 0.0602
629 Alpha-2B adrenergic receptor ADRA2B 0.0592
5455 Arylsulfatase A ARSA 0.0518
633 Penicillin-binding proteins 1A/1B pbpA 0.0461
118 Organic cation/carnitine transporter 2 SLC22A5 0.0457
4512 Cytochrome P450 3A4 CYP3A4 0.0433
23 D(1A) dopamine receptor DRD1 0.0425
4119 Cytochrome P450 2D6 CYP2D6 0.0393
4757 Cytochrome P450 2C9 CYP2C9 0.0384
1729 Solute carrier family 22 member 6 SLC22A6 0.0371
3941 Amine oxidase [flavin-containing] A MAOA 0.0365
766 Beta-2 adrenergic receptor ADRB2 0.0358
502 5-hydroxytryptamine 2A receptor HTR2A 0.0354
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0341
193 Beta-1 adrenergic receptor ADRB1 0.0337
1588 Multidrug resistance protein 1 ABCB1 0.0334
632 Alpha-1B adrenergic receptor ADRA1B 0.0332
4200 Cytochrome P450 1A2 CYP1A2 0.032
3939 Amine oxidase [flavin-containing] B MAOB 0.0311
831 D(2) dopamine receptor DRD2 0.0297
163 D(1B) dopamine receptor DRD5 0.0288
320 5-hydroxytryptamine 1A receptor HTR1A 0.0276
590 5-hydroxytryptamine 2C receptor HTR2C 0.0261
638 D(3) dopamine receptor DRD3 0.0246
1 Peptidoglycan synthetase ftsI ftsI 0.0235
4155 Peptidoglycan synthetase ftsI ftsI 0.0235
432 D(4) dopamine receptor DRD4 0.0234
725 5-hydroxytryptamine 1D receptor HTR1D 0.023
1385 Angiotensin-converting enzyme 2 ACE2 0.0222
645 Penicillin-binding protein 1A mrcA 0.0221
5805 Penicillin-binding protein 1A ponA 0.0221
6185 Penicillin-binding protein 1A mrcA 0.0221
6799 Penicillin-binding protein 1A pbpA 0.0221
6142 Solute carrier family 22 member 8 SLC22A8 0.022
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0218
885 5-hydroxytryptamine 1B receptor HTR1B 0.0211
146 Androgen receptor AR 0.021
492 Histamine H1 receptor HRH1 0.0203
587 Serum albumin ALB 0.0174
543 Penicillin-binding protein 1B mrcB 0.0174
6186 Penicillin-binding protein 1B ponB 0.0174
6822 Penicillin-binding protein 1b pbp1b 0.0174
6844 Penicillin-binding protein 1b pbp1b 0.0174
789 Alpha-1D adrenergic receptor ADRA1D 0.0169
471 Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) SLC6A14 0.0166
540 Sodium-dependent noradrenaline transporter SLC6A2 0.0166
824 Sodium-dependent serotonin transporter SLC6A4 0.0166
6016 Cytochrome P450 2C19 CYP2C19 0.0165
713 Sodium-dependent dopamine transporter SLC6A3 0.0165
436 5-hydroxytryptamine 2B receptor HTR2B 0.016
330 Spermidine synthase SRM 0.0149
3038 Spermidine synthase speE 0.0149
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0144
6013 Cytochrome P450 2E1 CYP2E1 0.0143
716 5-hydroxytryptamine 7 receptor HTR7 0.0142
3923 Cholinesterase BCHE 0.014
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0135
113 S-adenosylmethionine decarboxylase proenzyme AMD1 0.0128
453 S-adenosylmethionine synthetase isoform type-1 MAT1A 0.0126
334 S-adenosylmethionine synthetase isoform type-2 MAT2A 0.0126
411 Glycine N-methyltransferase GNMT 0.0122
131 Synaptic vesicular amine transporter SLC18A2 0.0118
358 Cystathionine beta-synthase CBS 0.0117
1024 Solute carrier family 22 member 11 SLC22A11 0.0114
1757 Myeloperoxidase MPO 0.0112
709 ATP-sensitive inward rectifier potassium channel 1 KCNJ1 0.0109
115 Penicillin-binding protein 2 mrdA 0.0108
6069 Penicillin-binding protein 2 mrdA 0.0108
6118 Penicillin-binding protein 2 penA 0.0108
6187 Penicillin-binding protein 2 pbpA 0.0108
6686 Penicillin-binding protein 2 pbp2 0.0108
6939 Penicillin-binding protein 2 mrdA 0.0108
7163 Penicillin-binding protein 2 pbpA 0.0108
6067 Penicillin binding protein 2a mecA 0.0107
56 Delta-aminolevulinic acid dehydratase ALAD 0.0106
2356 Delta-aminolevulinic acid dehydratase hemB 0.0106
3613 Delta-aminolevulinic acid dehydratase hemB 0.0106
3674 Delta-aminolevulinic acid dehydratase hemB 0.0106
4604 Liver carboxylesterase 1 CES1 0.01
6147 Solute carrier family 22 member 3 SLC22A3 0.01
6145 Solute carrier family 22 member 1 SLC22A1 0.0094
230 ATP-binding cassette transporter sub-family C member 8 ABCC8 0.0093
2544 Bacterial leucyl aminopeptidase Not Available 0.0092
4118 Cytochrome P450 3A5 CYP3A5 0.0091
3426 Glutamine synthetase glnA 0.0088
3987 Glutamine synthetase GLUL 0.0088
6164 POU domain, class 5, transcription factor 1 POU5F1 0.0084
6144 Solute carrier family 22 member 2 SLC22A2 0.0083
6113 MecA PBP2' (penicillin binding protein 2') mecA 0.0082
4924 Cytochrome P450 2C8 CYP2C8 0.008
6143 Solute carrier family 22 member 7 SLC22A7 0.0078
3917 Methylenetetrahydrofolate reductase MTHFR 0.0076
6070 Nischarin NISCH 0.0075
3809 Estrogen-related receptor gamma ESRRG 0.0072
6030 Cytochrome P450 2B6 CYP2B6 0.0071
1181 Alpha-1-acid glycoprotein 1 ORM1 0.007
2164 Multidrug resistance-associated protein 4 ABCC4 0.0069
3060 Leukotriene A-4 hydrolase LTA4H 0.0069
136 Estrogen receptor ESR1 0.0069
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0068
1141 Sialidase-1 NEU1 0.0068
64 Neuraminidase NA 0.0068
641 Neuraminidase NA 0.0068
2676 Neuraminidase NA 0.0068
3026 Neuraminidase NA 0.0068
3519 Neuraminidase NA 0.0068
6007 Neuraminidase NA 0.0068
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0066
1517 Beta-3 adrenergic receptor ADRB3 0.0063
6024 Cytochrome P450 1A1 CYP1A1 0.0063
6020 Aldehyde oxidase AOX1 0.0062
6107 Cytochrome P450 3A7 CYP3A7 0.0059
6160 Solute carrier organic anion transporter family member 3A1 SLCO3A1 0.0059
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0059
341 5-hydroxytryptamine 3 receptor HTR3A 0.0058
828 Phenylalanine-4-hydroxylase PAH 0.0058
3109 Phenylalanine-4-hydroxylase phhA 0.0058
6153 Solute carrier organic anion transporter family member 4A1 SLCO4A1 0.0058
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0057
159 Penicillin-binding protein 2B penA 0.0056
6121 Penicillin-binding protein 2B penA 0.0056
1256 5-hydroxytryptamine 6 receptor HTR6 0.0056
869 Estrogen receptor beta ESR2 0.0054
4252 Penicillin-binding protein 5 dacA 0.0054
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0053
5482 Sialidase-2 NEU2 0.0052
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0051
373 Transthyretin TTR 0.0051
3876 Aromatic-L-amino-acid decarboxylase DDC 0.005
617 Muscarinic acetylcholine receptor M2 CHRM2 0.005
707 72 kDa type IV collagenase MMP2 0.0048
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0048
738 Monocarboxylate transporter 1 SLC16A1 0.0048
332 Beta-lactamase blaZ 0.0047
2478 Beta-lactamase ampC 0.0047
2613 Beta-lactamase ampC 0.0047
2635 Beta-lactamase ampC 0.0047
2700 Beta-lactamase penP 0.0047
5445 Beta-lactamase blaB 0.0047
6019 Beta-lactamase SHV-7 0.0047
6701 Beta-lactamase cphA 0.0047
153 Dopamine beta-hydroxylase DBH 0.0047
124 Histamine H2 receptor HRH2 0.0046
528 5-hydroxytryptamine 1E receptor HTR1E 0.0046
509 Thymidine kinase TK 0.0046
570 Thymidine kinase TK 0.0046
2559 Thymidine kinase TK 0.0046
3430 Thymidine kinase tdk 0.0046
3518 Thymidine kinase TK 0.0046
5301 Thymidine kinase tdk 0.0046
5771 Thymidine kinase ORF36 0.0046
7009 Thymidine kinase ORF36 0.0046
3811 Cytochrome P450 19A1 CYP19A1 0.0045
5718 Cytochrome P450 2A6 CYP2A6 0.0045
3760 Penicillin-binding protein 5 precursor dacA 0.0042
338 DNA polymerase UL30 0.004
379 DNA polymerase UL54 0.004
697 DNA polymerase ORF28 0.004
2482 DNA polymerase 43 0.004
4104 DNA polymerase BALF5 0.004
6184 D-alanyl-D-alanine carboxypeptidase dacC dacC 0.004
6149 Solute carrier family 22 member 10 SLC22A10 0.004
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0039
65 Matrix metalloproteinase-9 Not Available 0.0039
6140 Ileal sodium/bile acid cotransporter SLC10A2 0.0039
833 Organic cation/carnitine transporter 1 SLC22A4 0.0039
867 Penicillin-binding protein 3 pbpC 0.0038
6119 Penicillin-binding protein 3 pbp3 0.0038
7154 Penicillin-binding protein 3 pbp3 0.0038
7157 Penicillin-binding protein 3 LMHCC_2184 0.0038
7162 Penicillin-binding protein 3 pbpB 0.0038
7172 Penicillin-binding protein 3 pbp3 0.0038
6151 Monocarboxylate transporter 10 SLC16A10 0.0037
4120 NADPH--cytochrome P450 reductase POR 0.0037
6167 Organic solute transporter subunit beta OSTB 0.0037
6166 Organic solute transporter subunit alpha OSTA 0.0037
20 Prostaglandin G/H synthase 1 PTGS1 0.0036
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0035
6155 ATP-binding cassette transporter sub-family C member 11 ABCC11 0.0034
734 D1 dopamine receptor-interacting protein calcyon CALY 0.0032
866 Large neutral amino acids transporter small subunit 2 SLC7A8 0.0032
862 Multidrug resistance-associated protein 1 ABCC1 0.0031
245 Large neutral amino acids transporter small subunit 1 SLC7A5 0.0029
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0029
6141 Sodium/bile acid cotransporter SLC10A1 0.0029
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.0028
6154 Multidrug and toxin extrusion protein 1 SLC47A1 0.0027
1636 Trace amine-associated receptor 1 TAAR1 0.0027
696 Kappa-type opioid receptor OPRK1 0.0026
465 Calmodulin CALM1 0.0023
6106 Cytochrome P450 2C18 CYP2C18 0.0022
2461 D-alanyl-D-alanine carboxypeptidase Not Available 0.0021
5756 D-alanyl-D-alanine carboxypeptidase dac 0.0021
3961 G protein-activated inward rectifier potassium channel 4 KCNJ5 0.0021
1656 CYP2B protein CYP2B 0.0021
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0019
521 ATP-binding cassette transporter sub-family C member 9 ABCC9 0.0018
233 Potassium channel subfamily K member 2 KCNK2 0.0017
631 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR 0.0017
3387 3-hydroxy-3-methylglutaryl-coenzyme A reductase mvaA 0.0017
132 ATP-binding cassette sub-family A member 1 ABCA1 0.0016
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0016
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0015
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0015
4112 Voltage-dependent L-type calcium channel subunit beta-4 CACNB4 0.0015
4114 Voltage-dependent L-type calcium channel subunit beta-3 CACNB3 0.0015
238 Peroxisome proliferator-activated receptor gamma PPARG 0.0015
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0014
781 ATP-sensitive inward rectifier potassium channel 11 KCNJ11 0.0014
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0014
333 Voltage-dependent L-type calcium channel subunit beta-1 CACNB1 0.0013
6100 BDNF/NT-3 growth factors receptor NTRK2 0.0013
158 Sodium channel protein type 1 subunit alpha SCN1A 0.0013
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0011
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0011
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0011
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0011
1618 High affinity nerve growth factor receptor NTRK1 0.001
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.001
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.001
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.001
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.001
776 Bile salt export pump ABCB11 0.001
164 Histamine H4 receptor HRH4 0.0009
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0008
467 Delta-type opioid receptor OPRD1 0.0007
1898 Cytochrome P450 1B1 CYP1B1 0.0005
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