Chlorpromazine

From ToxBankWiki

Chlorpromazine
Jump to: navigation, search

Executive Summary

Compound Chlorpromazine
Toxicities Cholestasis, cytotoxicity.
Mechanisms Chlorpromazine is activated by oxidation to electrophilic species that disrupt mitochondrial function and form adducts with cellular thiols. However, comparable toxicity is observed for both the parent compound and its reactive metabolite(s). The parent compound is classified as a promiscuous ligand that inserts into phospholipid membranes and modulates the activity of multiple membrane-bound proteins, for example complex V of the oxidative phosphorylation chain.
Comments This compound was selected to test the ability of cell-based assays to detect cholangiopathies that result from disruption of bile ducts.
Feedback Contact Gold Compound Working Group (GCWG)
Chlorpromazine
Chlorpromazine.png


Identifiers
Leadscope Id LS-105361
CAS 50-53-3
DrugBank DB00477
ChemSpider 2625
UNII U42B7VYA4P
Pathway DBs
KEGG D00270
Assay DBs
PubChem CID 2726
ChEMBL 71
Omics DBs
Open TG-Gate 00016
Properties
pKa 8.86
ToxCast Accepted yes
Toxic Effect Steatosis
ToxBank Accepted yes
Approved on 2011-06-28
Target dopamine, serotonin, adrenergic, histamine receptors
Toxicities Cholestasis,Cytotoxicity


Standard to Meet
In Vivo Data ? Compound Assessment
Adverse Events ? Receptor and ion channel – based toxicity

Chlorpromazine an antagonist of multiple biogenic amine receptors. Dose-limiting adverse events in most patients are related to the very low selectivity of this drug.

Chlorpromazine inhibits the hERG ion channel.

References:

-Thomas D, Wu K, Kathöfer S, et al. (June 2003). "The antipsychotic drug chlorpromazine inhibits HERG potassium channels". British Journal of Pharmacology 139 (3): 567–74.

Cytotoxicity, not hepatic

Skin discoloration and photosensitivity due to chlorpromazine are relatively common; life-threatening toxic epidermal necrolysis and Stevens-Johnson syndrome adverse events occur at a frequency of approximately of 1 per 300,000 patients. Together, these adverse events reflect to the chemical reactivity of chlorpromazine and the potential to form antigenic adducts with cellular proteins.

References:

-Anne Lee and John Thomson, Chaper 5, “Drug-induced skin reactions”, in Adverse Drug Reactions, 2nd edition (ISBN: 0 85369 601 2) © Pharmaceutical Press 2006
-Devi K, George S, Criton S, Suja V, Sridevi PK. Carbamazepine – The commonest cause of toxic epidermal necrolysis and Stevens-Johnson syndrome: A study of 7 years. Indian J Dermatol Venereol Leprol 2005;71:325-8.

Chlorpromazine causes adverse events to the reproductive system, and decrease in testicular weight is reproduced in animal models. While loss of organ weight could reflect cellular toxicity, the current explanation is an effect of dopamine antagonism on steroid hormone function.

References:

-Raji, et al. “Gonadal Responses to Antipsychotic Drugs: Chlorpromazine and Thioridazine Reversibly Suppress Testicular Functions in Albino Rat”, Int J Pharmacol 1: 287-295 2005.

Chlorpromazine induces life-threatening agranulocytosis and related leukopenias at a frequency of 1:1,000. The mechanisms assumed to cause these events are direct toxic effects on bone marrow, immune reaction to drug-induced antigens in the haematopoietic precursors, and/or peripheral destruction of cells.

References:

-Robert J. Flanagan and Louisa Dunk, “Haematological toxicity of drugs used in psychiatry”, Hum. Psychopharmacol Clin Exp 2008; 23: 27–41.

Hepato-toxicity
Chlorpromazine causes cholestasis with associated hepatitis, indicating hepatic necrosis, as well as cholangiopathies that span the range from ductopenia (mild bile duct disarray) to vanishing bile duct syndrome, which may be irreversible and lethal.

References:

-Manmeet S. Padda, Mayra Sanchez, Abbasi J. Akhtar, and James L. Boyer, “Drug-Induced Cholestasis”, Hepatology (2011) 53:1377-1387

The frequency of hepatotoxicities in aggregate is approximately 1%. Toxicity is more prevalent in patients with high CYP2D6 levels and less prevalent in patients with low sulfoxidation activity. Sulfoxidation is known to decrease toxicity of chlorpromazine and its metabolites.

References:

-Dominique Larrey and Georges Philippe Pageaux, “Genetic predisposition to drug-induced hepatotoxicity”, J Hepatology (1997) 26 (Suppl. 2): 12-21.

Toxicity Mechanisms ? The 7-hydroxychlorpromazine metabolite is a hydroquinoneimine. Both electrochemical and biochemical oxidation of this metabolite to the quinoneiminium ion has been demonstrated. When in vitro biochemical oxidation is performed in the presence of glutathione, glutathione traps the quinoneiminium ion to form the glutathionyl adduct at the 8-position. Cellular toxicity, and potentially generation of antigens, is inferred to occur via formation of similar adducts with reactive thiols on proteins. These results are consistent with a “normal” mechanism of activation to a quinone-type reactive intermediate via P450 oxidation.

References:

-Marilyn Neptune and Richard L. McCreery, “Chemical and Electrochemical Oxidation of 7-Hydroxychlorp”, J Med Chem (1978) 21: 362-368.
-Bo Wen, Mingyan Zhou, “Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s”,Chem-Biol Interactions 181 (2009) 220–226.

Cellular toxicity has been demonstrated for the parent drug in hepatocytic cell lines that are deficient in CYP2D6 and CYP1A2 and to human PMNs in cell culture. The current evidence implies that the parent drug is itself toxic with potency at least as great as the reactive metabolite. The chloroquinone parent is a diphenyl thioether and as such can be oxidized by weaker oxidants than the CYPs to generate free radicals.

References:

-M.A. Eghbal, S. Tafazoli, P. Pennefather, P.J. O’Brien, “Peroxidase catalysed formation of cytotoxic prooxidant phenothiazine free radicals at physiological pH”, Chem. Biol. Interact. 151 (2004) 43–51.
-Caroline Aninat, Ame´ lie Piton, Denise Glaise, Typhen Le Charpentier, Sophie Langoue, Fabrice Morel, Christiane Guguen-Guillouzo, and Andre´ Guillouzo, “Expression Of Cytochromes P450, Conjugating Enzymes And Nuclear Receptors In Human Hepatoma Heparg Cells”, Drug Metab Disp 34:75–83, 2006.
-Peter P. Kelder, Nicolaas J. De Mol, Bert A. 'T Hart, and Lambert H.M. Janssen, “Metabolic Activation Of Chlorpromazine By Stimulated Human Polymorphonuclear Leukocytes. Induction Of Covalent Binding Of Chlorpromazine To Nucleic Acids And Proteins”, Chem.-Biol. Interactions, 79 (1991) 15—30.

However, chlorpromazine is also a promiscuous protein inhibitor independent of any oxidative activation, and the pharmacological mechanism of action results at least in part from interaction of the drug with the plasma membrane, thereby disrupting membrane fluidity and the activity of membrane proteins. This promiscuity relates to toxicity, for example, in the inhibition of complex V of the oxidative phosphorylation chain.

References:

-Nora Andersona and Juergen Borlak, “Drug-induced phospholipidosis”, FEBS Letters 580 (2006) 5533–5540.
-P. Seeman, “Anti-schizophrenic drugs-membrane receptor sites of action”, Biochem. Pharmacol. 26:1741–1748 (1977).
-Sashi Nadanaciva, Autumn Bernal, Robert Aggeler, Roderick Capaldi, Yvonne Will, “Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays”, Toxicology in Vitro 21 (2007) 902-911.

Cell death occurs at concentrations of chlorpromazine that decrease the mitochondrial membrane potential and deplete glutathione.

References:

-Jinghai J. Xu, Peter V. Henstock, Margaret C. Dunn, Arthur R. Smith, Jeffrey R. Chabot, and David de Graaf, “Cellular Imaging Predictions of Clinical Drug-Induced Liver In”,Toxicological Sciences 105(1), 97–105 (2008).

The propensity of chlorpromazine for cholangiopathies implies exposure to canalicular epithelial cells. Toxicity via both chlorpromazine and its 7-hydroxy metabolite is consistent with this model. There was initial evidence that chlorpromazine might be actively pumped from hepatocytes into the bile ducts by the MDR-1 (P-gp) pump. Recent data, however, indicates that membranes are highly permeable to chlorpromazine but that there is no active transport. Is probable that chlorpromazine accumulates in the bile by physical association with bile salts and phospholipids. While this does not necessarily increase the concentration of free drug in the bile, it may in some way increase exposure to canalicular cells.

References:

-Scott G. Summerfield, Kevin Read, David J. Begley, Tanja Obradovic, Ismael J. Hidalgo, Sara Coggon, Ann V. Lewis, Rod A. Porter, and Phil Jeffrey, “Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction”, JPET 322:205–213, 2007.

Chlorpromazine inhibits BSEP (another example of promiscuity) but at concentrations that exceed its IC50 for cellular toxicity.

References:

-M Horikawa, Y Kato, CA Tyson, and Y Sugiyama, “Potential Cholestatic Activity of Various Therapeutic Agents Assessed by Bil Canalicular Membrane Vesicles Isolated from Rats and Humans”, Drug Metab Pharmacokin (2003) 18: 16-22.
Therapeutic Target ? Antagonist for biogenic amine receptors: dopamine D1,D2,D3,D3; serotonin

5-HT-1, 5-HT-2; histamine H1; adrenergic alpha-1 and alpha-2; muscarinic M1 and M2.

Human Adverse Events

The following data table has been mined from the Adverse Events Reporting System (AERS) of the US FDA. Significant human liver events. The first column ("# Reports") is the number of reports found for the corresponding adverse event reported in the third column ("Adverse Event"). The second column ("Report:Baseline Ratio") is ratio calculated from the number of reports ("# Reports") divided by a calculated expected statistical baseline number of reports.

# Reports Report:Baseline Ratio Adverse Event
1 31.9205 hepato-lenticular degeneration
2 4.71378 liver injury
2 9.14854 vanishing bile duct syndrome

FDA and Label Information

The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products

This next url will perform a search in the FDA's system for all labels for products that contain "Chlorpromazine" as an active ingredient.
FDA Label Search

PubMed references

The following resource link will perform a PubMed query for the terms "Chlorpromazine" and "liver toxicity".
Chlorpromazine Search

The table listed below contains a summarized listing of toxic effect information leveraged from the 6th European Framework Programme project LIINTOP. For a complete listing of the Gold Compound evaluation criteria please see the Gold Compound Evaluation and Comments immediately following the summary table below.

SMILES CN(C)CCCN1C2=CC=CC=C2SC3=C1C=C(C=C3)Cl
InChI

InChI=1S/C17H19ClN2S/c1-19(2)10-5-11-20-14-6-3-4-7-16(14)21-17-9-8-13(18)12-15(17)20/h3-4,6-9,12H,5,10-11H2,1-2H3

InChI-Key

ZPEIMTDSQAKGNT-UHFFFAOYSA-N

Summary Hepatotoxic Effects from the LIINTOP FP6 Program
Hepatocellular necrosis.gif Apoptosis.gif Transporter inhibition.gif Cholestatic.gif Steatotic.gif Phospholipidosis.gif Hepatocyte function.gif Mithochondria impairment.gif Oxidative stress.gif DNA synthesis genotoxicity.gif Covalent binding.gif Idiosyncrasia metabolic.gif Idiosyncrasia immune.gif Bioactivation required.gif LIINTOP severity.gif References
+ + + + 2

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]

References

  1. Cullen, J.M., 2005. Mechanistic classification of liver injury. Toxicol. Pathol. 33, 6–8.
  2. Geier, A., Dietrich, C.G., Gerloff, T., Haendly, J., Kullak-Ublick, G.A., Stieger, B., Meier, P.J., Matern, S., Gartung, C., 2003. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim. Biophys. Acta 1609, 87–94.
  3. Loranger, A., Barriault, C., Yousef, I.M., Tuchweber, B., 1996. Structural and functional alterations of hepatocytes during transient phalloidin-induced cholestasis in the rat. Toxicol. Appl. Pharmacol. 137, 100–111.
  4. Pauli-Magnus, C., Meier, P.J., 2006. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778–787.
  5. Rolo, A.P., Oliveira, P.J., Seica, R., Santos, M.S., Moreno, A.J., Palmeira, C.M., 2002. Disruption of mitochondrial calcium homeostasis after chronic alphanaphthylisothiocyanate administration: relevance for cholestasis. J. Invest. Med. 50, 193–200.
  6. Roman, I.D., Fernandez-Moreno, M.D., Fueyo, J.A., Roma, M.G., Coleman, R., 2003. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol. Sci. 71, 276–281.
  7. Sokol, R.J., Dahl, R., Devereaux, M.W., Yerushalmi, B., Kobak, G.E., Gumpricht, E., 2005. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J. Pediatr. Gastroenterol. Nutr. 41, 235–243.
  8. Thibault, N., Claude, J.R., Ballet, F., 1992. Actin filament alteration as a potential marker for cholestasis: a study in isolated rat hepatocyte couplets. Toxicology 73, 269–279.
  9. Zollner, G., Trauner, M., 2008. Mechanisms of cholestasis. Clin. Liver Dis. 12, 1–26 (vii).
  10. Chatman, L.A., Morton, D., Johnson, T.O., Anway, S.D., 2009. A strategy for risk management of drug-induced phospholipidosis. Toxicol. Pathol. 37, 997–1005.
  11. Halliwell, W.H., 1997. Cationic amphiphilic drug-induced phospholipidosis. Toxicol. Pathol. 25, 53–60.
  12. Kasahara, T., Tomita, K., Murano, H., Harada, T., Tsubakimoto, K., Ogihara, T., Ohnishi, S., Kakinuma, C., 2006. Establishment of an in vitro high-throughput screening assay for detecting phospholipidosis-inducing potential. Toxicol. Sci. 90, 133–141.
  13. Nioi, P., Perry, B.K., Wang, E.J., Gu, Y.Z., Snyder, R.D., 2007. In vitro detection of druginduced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol. Sci. 99, 162–173.
  14. Nonoyama, T., Fukuda, R., 2008. Drug-induced phospholipidosis – pathological aspects and its prediction. J. Toxicol. Pathol. 21, 9–34.
  15. Pappu, A., Hostetler, K.Y., 1984. Effect of cationic amphiphilic drugs on the hydrolysis of acidic and neutral phospholipids by liver lysosomal phospholipase A. Biochem. Pharmacol. 33, 1639–1644.
  16. Reasor, M.J., Hastings, K.L., Ulrich, R.G., 2006. Drug-induced phospholipidosis: issues and future directions. Expert Opin. Drug Saf. 5, 567–583.
  17. Reasor, M.J., Kacew, S., 2001. Drug-induced phospholipidosis: are there functional consequences? Exp. Biol. Med. (Maywood) 226, 825–830.
  18. Sawada, H., Takami, K., Asahi, S., 2005. A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol. Sci. 83, 282–292.
  19. Hynes, J., Marroquin, L.D., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B., Will, Y., 2006. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186–200.
  20. Johannsen, D.L., Ravussin, E., 2009. The role of mitochondria in health and disease. Curr. Opin. Pharmacol. 9, 780–786.
  21. Jones, D.P., Lemasters, J.J., Han, D., Boelsterli, U.A., Kaplowitz, N., 2010. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol. Interv. 10, 98–111.
  22. Labbe, G., Pessayre, D., Fromenty, B., 2008. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335–353.
  23. Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.
  24. Geier, A., Dietrich, C.G., Gerloff, T., Haendly, J., Kullak-Ublick, G.A., Stieger, B., Meier, P.J., Matern, S., Gartung, C., 2003. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim. Biophys. Acta 1609, 87–94.
  25. Loranger, A., Barriault, C., Yousef, I.M., Tuchweber, B., 1996. Structural and functional alterations of hepatocytes during transient phalloidin-induced cholestasis in the rat. Toxicol. Appl. Pharmacol. 137, 100–111.
  26. Marion, T.L., Leslie, E.M., Brouwer, K.L., 2007. Use of sandwich-cultured hepatocytes to evaluate impaired bile acid transport as a mechanism of drug-induced hepatotoxicity. Mol. Pharm. 4, 911–918.
  27. Palmeira, C.M., Rolo, A.P., 2004. Mitochondrially-mediated toxicity of bile acids. Toxicology 203, 1–15.
  28. Pauli-Magnus, C., Meier, P.J., 2006. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778–787.
  29. Rolo, A.P., Oliveira, P.J., Seica, R., Santos, M.S., Moreno, A.J., Palmeira, C.M., 2002. Disruption of mitochondrial calcium homeostasis after chronic alphanaphthylisothiocyanate administration: relevance for cholestasis. J. Invest. Med. 50, 193–200.
  30. Roman, I.D., Fernandez-Moreno, M.D., Fueyo, J.A., Roma, M.G., Coleman, R., 2003. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol. Sci. 71, 276–281.
  31. Sokol, R.J., Dahl, R., Devereaux, M.W., Yerushalmi, B., Kobak, G.E., Gumpricht, E., 2005. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J. Pediatr. Gastroenterol. Nutr. 41, 235–243.
  32. Thibault, N., Claude, J.R., Ballet, F., 1992. Actin filament alteration as a potential marker for cholestasis: a study in isolated rat hepatocyte couplets. Toxicology 73, 269–279.
  33. Zollner, G., Trauner, M., 2008. Mechanisms of cholestasis. Clin. Liver Dis. 12, 1–26 (vii).

Standard to Meet
PK-ADME ? Compound Assessment
PK parameters ? > 90% to plasma proteins, primarily albumin


Vd = 20 L/kg (drugbank)
Half life 12 hrs

References:

-Andre J. Jackson (2001) Biopharm. Drug Dispos. 22: 179–190

Cmax = 0.8 uM at maximum recommended dose of 50 umol/kg (17 mg/kg)

References:

-Jinghai J. Xu, Peter V. Henstock, Margaret C. Dunn, Arthur R. Smith, Jeffrey R. Chabot, and David de Graaf, “Cellular Imaging Predictions of Clinical Drug-Induced Liver In”,TOXICOLOGICAL SCIENCES 105(1), 97–105 (2008).

PK parameters are dose-proportional within error in the range 0.4-17 mg/kg. Coefficient of variation for parent drug Cmax is high (50-75%). Major metabolites are found in plasma at concentrations comparable to the parent compound and with equal or longer elimination half-lives.

References

-P. K. Yeung, J. W. Hubbard, E. D. Korchinski and K. K. Midha, “Pharmacokinetics of chlorpromazine and key metabolites”, Eur J Clin Pharm (1993) 45:563-569.

Mono- and di-N-demethylation of chlorpromazine is observed in human liver microsomes (kinetics of demethylation are reported).

References

-Jacek Wójcikowski, Władysława A. Daniel (2010) “Influence of antidepressant drugs on

chlorpromazine metabolism in human liver – an in vitro study”, Pharmacological Reports 62:1062-1069

A single oral dose of 100 mg gave average parameters across 57 volumteers of:

Cmax:48 ng/mL± 34 ng/mL
Tmax:2.6 h± 1.4 h
T1/2:13 h± 5 h
AUCinf:420 ng x h/mL± 350 ng x h/mL

References

-Ney Carter Borges, Vinicius Marcondes Rezende, Jose Marcos Santana , Ricardo Pereira Moreira,

Roberto Fernandes Moreira, Patrícia Moreno, Diego Carter Borges, José Luiz Donato, Ronilson Agnaldo Moreno, “Chlorpromazine quantification in human plasma by UPLC–electrospray ionization tandem mass spectrometry. Application to a comparative pharmacokinetic study”, Journal of Chromatography B (2011) 879:3728– 3734

Therapeutic window ? Maximum recommended dose in humans (oral) 17 mg/kg (52 umol/kg)
LD50 (mg/kg)
SpeciesOralIntraperitonealIntravenous
Mouse37611531
Rat-58-
Dog--37
Metabolically activated ? Extensively metabolized in the liver and kidneys by cytochrome P450 isozymes CYP2D6 (major pathway) plus CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolites have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus produces dihydroquinonimines. The N-dimethylaminopropyl side chain undergoes demethylation and is then metabolized to an N-oxide.

Cmax values are approximately equal for chlorpromazine, 7-hydroxy-chlorpromazine, chlorpromazine N-oxide, and chlorpromazine sulfoxide. Glucuronide and sulfate adducts with 7-hydroxychlorpromazine are the major species after first pass metabolism, approximately 2-fold higher than other species

CYP2D6 and CYP1A2 are the major sources of 7-hydroxychlorpromazine , with CYP2D6 having approximately 20-fold higher intrinsic activity.

References:

-P. K.-E Yeung, J. W. Hubbard, E. D. Korchinski, and K. K. Midha, “Pharmacokinetics of chlorpromazine and key metabolites”, Eur J Clin Pharmacol (1993) 45:563-569.
-Kazuyoshi Yoshii, Kaoru Kobayashi, Mihoko Tsumuji, Masayoshi Tani, Noriaki Shimada, and Kan Chiba, “IdentiÞcation of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes”, Life Sciences 67 (2000) 175Ð184.

Metabolic activation is apparently not necessary for toxicity (see discussion of toxicity mechanism above).

Standard to Meet
Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? Series: GSE19662

Status: Public on Jan 05 2010
Title: Identification of biomarkers that distinguish chemical contaminants using a gradient feature selection method
Organism(s) Rattus norvegicus

Open TG-GATEs Human Liver
Status: Public on Feb 25, 2011
Title: Genomics Assisted Toxicity Evaluation system study - Human Hepatocytes
Organism(s): Homo Sapiens

References:

-Takeki Uehara, Atsushi Ono, Toshiyuki Maruyama, Ikuo Kato, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani. The Japanese toxicogenomics project: application of toxicogenomics. Molecular nutrition & food research. 2010 Feb;54(2): 218-27 pmid:20041446

Series: GSE8858
Study: Title Liver Pharmacology and Xenobiotic Response Repertoire
Organsim(s): Rattus norvegicus

References:

-Natsoulis G, Pearson CI, Gollub J, P Eynon B et al. The liver pharmacological and xenobiotic gene response repertoire. Mol Syst Biol 2008;4:175. pmid:18364709
Proteomics profiles known. ?
Metabonomics profiles known. ?
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ?
IC50’s
B-adrenoceptor system200 uM
Mas D receptor2.7 μM
D2 receptor affinity1.7nM
D4 receptor affinity15.7nM
Current Medicinal Chemistry – 1995 Vol. 1, No. 6 pg 477
Observed IC50 for in vitro cellular toxicity studies. ? >99% depletion of GSH and loss mitochondrial membrane potential at 84 uM in HEPG2 cells. This concentration was chosen as 100x the Cmax at the maximum recommended dose.

References:

-Jinghai J. Xu, Peter V. Henstock, Margaret C. Dunn, Arthur R. Smith, Jeffrey R. Chabot, and David de Graaf, “Cellular Imaging Predictions of Clinical Drug-Induced Liver In”,Toxicological Sciences 105(1), 97–105 (2008).

Inhibition of BSEP: IC50 = 500 uM (rat) Inhibition of MRP2: IC50 = 260 uM (rat, equally or less potent vs. human)

References:

-M Horikawa, Y Kato, CA Tyson, and Y Sugiyama, “Potential Cholestatic Activity of Various Therapeutic Agents Assessed by Bil Canalicular Membrane Vesicles Isolated from Rats and Humans”, Drug Metab Pharmacokin (2003) 18: 16-22.
IC50 for cell viability
Rat hepatocyte45 uM
3T3 cells100 uM
Hela44 uM
HepG235 uM

References:

-Wang et al. The Journal of Toxicological Sciences (2002) 27: 229-237.

IC50 for inhibition of Complex V = 26 uM

References:

-Sashi Nadanaciva, Autumn Bernal, Robert Aggeler, Roderick Capaldi, Yvonne W, “Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays”, Toxicology in Vitro 21 (2007) 902-911.

Chlorpromazine is intrinsically highly membrane permeable and is not a substrate for P-gp (MDR-1). Data on possible transport of metabolites was not found.

References

-Scott G. Summerfield, Kevin Read, David J. Begley, Tanja Obradovic, Ismael J. Hidalgo, Sara Coggon, Ann V. Lewis, Rod A. Porter, and Phil Jeffrey, “Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction”, JPET 322:205–213, 2007.

Standard to Meet
Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? Yes - Included in ToxCast Phase I and II Chemicals List.
Substance stability. ? Protect from light.
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Chlorpromazine water solubility: 0.0026 mg/ml (24°C) [YALKOWSKY,SH & DANNENFELSER,RM (1992) from SRC PhysProp Database]


chlorpromazine estimated intrinsic solubility : 1.7435e-3 mg/ml
chlorpromazine estimated solubility in pure water at pH 9.03: 5.5506e-3 mg/ml
chlorpromazine estimated solubility in water at pH 7.4: 0.15 mg/ml [Calculations performed using ACD/PhysChem v 9.14]
Solubility as a function of pH and other parameters available on the wiki
chlorpromazine hydrochloride water solubility: 50 mg/ml Sigma C8138 Product details

Solubility in DMSO 100 times buffer solubility. ?
Vessel binding properties. ?
Vapor pressure. (Non-volatile) ? Chlorpromazine estimated vapor pressure: 5.17E-06 mmHg (Calculation performed using EPI Suite v4.10)

Calculated/Predicted Properties

Water Solubility Results
pH Sol,mg/ml 18+,19+ 19+ 0 Graph
2 2.2 - 100 - Chlorpromazine solubility.png
5.5 1.88 - 100 -
6.5 0.81 - 99.9 0.1
7.4 0.15 - 98.9 1.1
10 2.15E-3 - 18.9 81.1
Summary Solubility Data
Intrinsic Solubility,mg/ml 1.7435E-3
Intrinsic Solubility,log(S,mol/l) -5.2622
Solubility in Pure Water at pH = 9.03,mg/ml 5.5506E-3
Calculations performed using ACD/PhysChem v 9.14
LogD Results
pH LogD Graph
2 1.71 Chlorpromazine logd.png
5.5 1.78
6.5 2.15
7.4 2.87
10 4.72
Calculations performed using ACD/PhysChem v 9.14
Single-valued Properties
Property Value Units Error
LogP 4.82 0.89
MW 318.86 -
PSA 31.78 -
FRB 4 -
HDonors 0 -
HAcceptors 2 -
Rule Of 5 0 -
Molar Refractivity 92.75 cm3 0.3
Molar Volume 262.91 cm3 3
Parachor 686.91 cm3 6
Index of Refraction 1.62 0.02
Surface Tension 46.6 dyne/cm 3
Density 1.21 g/cm3 0.06
Polarizability 36.77 10E-24 cm3 0.5
Calculations performed using ACD/PhysChem v 9.14
Property Name Value Units Source
pKa 8.86 SPARC v4.5
Estimated VP 5.17E-06 mm Hg EPI Suite v4.10
Estimated VP 0.0006893 Pa EPI Suite v4.10
Estimated Water Solubility 0.1804 mg/L EPI Suite v4.10
WATERNT Frag Water Solubility Estimate 2.1806 mg/L EPI Suite v4.10
pKa Results
Acidic/Basic Acidic/Basic Aparrent pKa Value Error
19 MB 9.41 0.28
18 B -1.28 0.2
A = Acidic
B = Basic
MA = Most Acidic
MB = Most Basic
Calculations performed using ACD/PhysChem v 9.14

Authors of this ToxBank wiki page

David Bower, Egon Willighagen, Matthew Clark
Personal tools
Namespaces
Variants
Actions
Navigation
Hepatotoxins
Cardiotoxins
Renal Toxins
Special Substances
Undifferentiated Stem Cells
hiPSC Lines
Liver Cell Lines
iPS-derived Cardiomyocytes
Reagents (Growth Factors)
Reagents (Antibodies)
Reagents (Others)
Suppliers (Cells)
Toolbox