Lack of cataleptogenic potentiation with non-imidazole H3 receptor antagonists reveals potential drug-drug interactions between imidazole-based H3 receptor antagonists and antipsychotic drugs.
Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.
Zhang
Min
M
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, AP9A, R4N5, 100 Abbott Park, Abbott Park, IL 60064-6115, USA. min.zhang@abbott.com
Ballard
Michael E
ME
Pan
Liping
L
Roberts
Stanley
S
Faghih
Ramin
R
Cowart
Marlon
M
Esbenshade
Tim A
TA
Fox
Gerard B
GB
Decker
Michael W
MW
Hancock
Art A
AA
Rueter
Lynne E
LE
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001572:Benzofurans / Q000737:chemistry / Q000493:pharmacokinetics; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002385:Cataplexy / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004338:Drug Combinations; D004357:Drug Synergism; D006220:Haloperidol / Q000493:pharmacokinetics; D006632:Histamine / Q000378:metabolism*; D006633:Histamine Antagonists / Q000737:chemistry / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics; D007654:Ketoconazole / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D018967:Risperidone / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000188:drug therapy
D014150:Antipsychotic Agents; D001572:Benzofurans; D004338:Drug Combinations; D006633:Histamine Antagonists; D007093:Imidazoles; D010880:Piperidines; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C115705:ciproxifan; D006632:Histamine; C496397:benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-; D003577:Cytochrome P-450 Enzyme System; C052075:thioperamide; D006220:Haloperidol; D018967:Risperidone; D007654:Ketoconazole