DT-Web

DB00611 - Butorphanol


Identification
Name Butorphanol
Accession Number DB00611 (APRD00835)
Type small molecule
Description A synthetic morphinan analgesic with narcotic antagonist action. It is used in the management of severe pain. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 327.4605
Groups illicit
Monoisotopic Weight 327.219829177
Pharmacology
Indication For the relief of moderate to severe pain.
Mechanism of action The exact mechanism of action is unknown, but is believed to interact with an opiate receptor site in the CNS (probably in or associated with the limbic system). The opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but may also be a result of other mechanisms. Butorphanol is a mixed agonist-antagonist that exerts antagonistic or partially antagonistic effects at mu opiate receptor sites, but is thought to exert its agonistic effects principally at the kappa and sigma opiate receptors.
Absorption Rapidly absorbed after intramuscular injection and peak plasma levels are reached in 20-40 minutes. The absolute bioavailability is 60-70% and is unchanged in patients with allergic rhinitis. In patients using a nasal vasoconstrictor (oxymetazoline) the fraction of the dose absorbed was unchanged, but the rate of absorption was slowed. Oral bioavailability is only 5-17% because of extensive first-pass metabolism.
Protein binding Serum protein binding is approximately 80%.
Biotransformation Extensively metabolized in the liver. The pharmacological activity of butorphanol metabolites has not been studied in humans; in animal studies, butorphanol metabolites have demonstrated some analgesic activity.
Route of elimination Butorphanol is extensively metabolized in the liver. Elimination occurs by urine and fecal excretion.
Toxicity The clinical manifestations of butorphanol overdose are those of opioid drugs in general. The most serious symptoms are hypoventilation, cardiovascular insufficiency, coma, and death.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Alvimopan Opioid analgesics such as butorphanol may enhance the adverse/toxic effect of alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. According to alvimopan prescribing information, alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Monitor for increased alvimopan adverse effects in patients using opioids prior to alvimopan.
Droperidol Droperidol may enhance the CNS depressant effect of butorphanol. Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use.
Triprolidine The CNS depressants, Triprolidine and Butorphanol, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food Interactions
  • Avoid alcohol.

Targets


Kappa-type opioid receptor
Name Kappa-type opioid receptor
Gene Name OPRK1
Pharmacological action yes
Actions agonist
References
  • Vivian JA, DeYoung MB, Sumpter TL, Traynor JR, Lewis JW, Woods JH: kappa-Opioid receptor effects of butorphanol in rhesus monkeys. J Pharmacol Exp Ther. 1999 Jul;290(1):259-65. - Pubmed
  • Park Y, Jang CG, Ho IK, Ko KH: kappa-opioid agonist stimulated regional distribution of [(35)S]GTPgammas binding in butorphanol continuously infused rat. Brain Res Bull. 2000 May 1;52(1):17-20. - Pubmed
  • Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. - Pubmed
  • Fan LW, Tanaka S, Park Y, Sasaki K, Ma T, Tien LT, Rockhold RW, Ho IK: Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding. Brain Res. 2002 Dec 27;958(2):277-90. - Pubmed
  • Commiskey S, Fan LW, Ho IK, Rockhold RW: Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16. Epub 2005 Jun 8. - Pubmed
  • Picker MJ, Benyas S, Horwitz JA, Thompson K, Mathewson C, Smith MA: Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther. 1996 Dec;279(3):1130-41. - Pubmed
  • Wakabayashi H, Tokuyama S, Ho IK: Simultaneous measurement of biogenic amines and their metabolites in rat brain regions after acute administration of and abrupt withdrawal from butorphanol or morphine. Neurochem Res. 1995 Oct;20(10):1179-85. - Pubmed
  • Narita M, Feng Y, Makimura M, Hoskins B, Ho IK: Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547-50. - Pubmed
  • Ohta S, Niwa M, Nozaki M, Tsurumi K, Shimonaka H, Tanahashi T, Uematsu H, Yamamoto M, Fujimura H: [Kappa-type opioid receptor in human placental membrane] Masui. 1989 Oct;38(10):1293-300. - Pubmed
  • Walsh SL, Chausmer AE, Strain EC, Bigelow GE: Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology (Berl). 2008 Jan;196(1):143-55. Epub 2007 Oct 2. - Pubmed
DTHybrid score 0.7602
Delta-type opioid receptor
Name Delta-type opioid receptor
Gene Name OPRD1
Pharmacological action yes
Actions agonist
References
  • Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. - Pubmed
  • Fan LW, Tanaka S, Park Y, Sasaki K, Ma T, Tien LT, Rockhold RW, Ho IK: Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding. Brain Res. 2002 Dec 27;958(2):277-90. - Pubmed
  • Commiskey S, Fan LW, Ho IK, Rockhold RW: Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16. Epub 2005 Jun 8. - Pubmed
  • Picker MJ, Benyas S, Horwitz JA, Thompson K, Mathewson C, Smith MA: Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther. 1996 Dec;279(3):1130-41. - Pubmed
  • Wakabayashi H, Tokuyama S, Ho IK: Simultaneous measurement of biogenic amines and their metabolites in rat brain regions after acute administration of and abrupt withdrawal from butorphanol or morphine. Neurochem Res. 1995 Oct;20(10):1179-85. - Pubmed
  • Narita M, Feng Y, Makimura M, Hoskins B, Ho IK: Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547-50. - Pubmed
  • Walsh SL, Chausmer AE, Strain EC, Bigelow GE: Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology (Berl). 2008 Jan;196(1):143-55. Epub 2007 Oct 2. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.7831
Mu-type opioid receptor
Name Mu-type opioid receptor
Gene Name OPRM1
Pharmacological action yes
Actions partial antagonist
References
  • Vivian JA, DeYoung MB, Sumpter TL, Traynor JR, Lewis JW, Woods JH: kappa-Opioid receptor effects of butorphanol in rhesus monkeys. J Pharmacol Exp Ther. 1999 Jul;290(1):259-65. - Pubmed
  • Fan LW, Tanaka S, Tien LT, Ma T, Rockhold RW, Ho IK: Withdrawal from dependence upon butorphanol uniquely increases kappa(1)-opioid receptor binding in the rat brain. Brain Res Bull. 2002 Jun;58(2):149-60. - Pubmed
  • Fan LW, Tanaka S, Park Y, Sasaki K, Ma T, Tien LT, Rockhold RW, Ho IK: Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding. Brain Res. 2002 Dec 27;958(2):277-90. - Pubmed
  • Commiskey S, Fan LW, Ho IK, Rockhold RW: Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16. Epub 2005 Jun 8. - Pubmed
  • Picker MJ, Benyas S, Horwitz JA, Thompson K, Mathewson C, Smith MA: Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther. 1996 Dec;279(3):1130-41. - Pubmed
  • Wakabayashi H, Tokuyama S, Ho IK: Simultaneous measurement of biogenic amines and their metabolites in rat brain regions after acute administration of and abrupt withdrawal from butorphanol or morphine. Neurochem Res. 1995 Oct;20(10):1179-85. - Pubmed
  • Picker MJ: Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists. J Pharmacol Exp Ther. 1997 Dec;283(3):1009-17. - Pubmed
  • Narita M, Feng Y, Makimura M, Hoskins B, Ho IK: Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547-50. - Pubmed
  • Walsh SL, Chausmer AE, Strain EC, Bigelow GE: Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology (Berl). 2008 Jan;196(1):143-55. Epub 2007 Oct 2. - Pubmed
DTHybrid score 0.9578

Predictions


Id Partner name Gene Name Score
1716 Tripartite motif-containing protein 13 TRIM13 0.115
4512 Cytochrome P450 3A4 CYP3A4 0.1082
4119 Cytochrome P450 2D6 CYP2D6 0.1049
1262 Corticotropin-lipotropin POMC 0.0832
6107 Cytochrome P450 3A7 CYP3A7 0.0588
1588 Multidrug resistance protein 1 ABCB1 0.0474
4118 Cytochrome P450 3A5 CYP3A5 0.0443
4137 Nociceptin receptor OPRL1 0.0389
4924 Cytochrome P450 2C8 CYP2C8 0.0385
319 Opioid receptor, sigma 1 OPRS1 0.0343
4757 Cytochrome P450 2C9 CYP2C9 0.0338
174 Sigma 1-type opioid receptor SIGMAR1 0.0337
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0291
6180 UDP-glucuronosyltransferase 2B4 UGT2B4 0.0287
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0278
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0247
6030 Cytochrome P450 2B6 CYP2B6 0.024
824 Sodium-dependent serotonin transporter SLC6A4 0.0188
540 Sodium-dependent noradrenaline transporter SLC6A2 0.0186
5838 Transient receptor potential cation channel subfamily V member 3 TRPV3 0.0176
2162 Transient receptor potential cation channel subfamily M member 8 TRPM8 0.0176
1944 Transient receptor potential cation channel subfamily A member 1 TRPA1 0.0176
6016 Cytochrome P450 2C19 CYP2C19 0.0168
1291 cAMP response element-binding protein CREB1 0.0166
341 5-hydroxytryptamine 3 receptor HTR3A 0.0164
4210 Toll-like receptor 4 TLR4 0.015
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.014
587 Serum albumin ALB 0.0137
392 Voltage-dependent P/Q-type calcium channel subunit alpha-1A CACNA1A 0.0136
5878 Alpha-7 nicotinic cholinergic receptor subunit CHRFAM7A 0.0127
4200 Cytochrome P450 1A2 CYP1A2 0.0121
6181 UDP-glucuronosyltransferase 1-8 UGT1A8 0.0118
590 5-hydroxytryptamine 2C receptor HTR2C 0.0113
6106 Cytochrome P450 2C18 CYP2C18 0.0107
20 Prostaglandin G/H synthase 1 PTGS1 0.01
465 Calmodulin CALM1 0.0097
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0094
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.009
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0088
6145 Solute carrier family 22 member 1 SLC22A1 0.0084
136 Estrogen receptor ESR1 0.0082
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0079
3811 Cytochrome P450 19A1 CYP19A1 0.0079
6078 Neuronal acetylcholine receptor subunit beta-4 CHRNB4 0.0065
4120 NADPH--cytochrome P450 reductase POR 0.006
6079 Neuronal acetylcholine receptor subunit alpha-3 CHRNA3 0.0058
458 Neuronal acetylcholine receptor subunit alpha-10 CHRNA10 0.0055
5718 Cytochrome P450 2A6 CYP2A6 0.0053
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0051
318 Alpha-2A adrenergic receptor ADRA2A 0.0048
502 5-hydroxytryptamine 2A receptor HTR2A 0.0046
439 Glutamate [NMDA] receptor subunit epsilon-4 GRIN2D 0.0045
492 Histamine H1 receptor HRH1 0.0045
6100 BDNF/NT-3 growth factors receptor NTRK2 0.0044
505 Glutamate [NMDA] receptor subunit epsilon-3 GRIN2C 0.0044
320 5-hydroxytryptamine 1A receptor HTR1A 0.0043
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0041
401 Glutamate [NMDA] receptor subunit zeta-1 GRIN1 0.0039
837 Glutamate [NMDA] receptor subunit epsilon-1 GRIN2A 0.0039
94 5-hydroxytryptamine 4 receptor HTR4 0.0035
6013 Cytochrome P450 2E1 CYP2E1 0.0035
1618 High affinity nerve growth factor receptor NTRK1 0.0034
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.0033
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.0033
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.0033
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0027
885 5-hydroxytryptamine 1B receptor HTR1B 0.0025
789 Alpha-1D adrenergic receptor ADRA1D 0.0023
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0022
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0021
617 Muscarinic acetylcholine receptor M2 CHRM2 0.0019
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0018
556 Alpha-1A adrenergic receptor ADRA1A 0.0018
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