Perazine at therapeutic drug concentrations inhibits human cytochrome P450 isoenzyme 1A2 (CYP1A2) and caffeine metabolism--an in vitro study. 2009

Jacek Wójcikowski, and Władysława A Daniel
Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. wojcikow@if-pan.krakow.pl

The aim of the present study was to estimate the inhibitory effect of perazine, a phenothiazine neuroleptic with piperazine structure in a side chain, on human CYP1A2 activity measured as a rate of caffeine 3-N- and 1-N-demethylation. Moreover, the influence of perazine on other caffeine metabolic pathways such as 7-N-demethylation (CYP1A2, CYP2C8/9, CYP3A4) and 8-hydroxylation (CYP3A4, CYP1A2, CYP2C8/9) was also determined. The Dixon analysis showed that in both human liver microsomes and Supersomes CYP1A2 perazine potently and to a similar degree inhibited caffeine 3-N-demethylation (K(i) = 3.5 microM) and 1-N-demethylation (K(i) = 5 microM). Perazine moderately diminished the rate of caffeine 7-N-demethylation in Supersomes CYP1A2 (K(i) = 11.5 microM) and liver microsomes (K(i) = 20 microM), and attenuated C-8-hydroxylation (K(i) = 15.5 microM) in Supersomes CYP1A2. On the other hand, perazine weakly inhibited caffeine C-8-hydroxylation in liver microsomes (K(i) = 98 microM). About 80% of basal CYP1A2 activity was reduced by the therapeutic concentrations of perazine (5-10 microM). The obtained results show that perazine at its therapeutic concentrations is a potent inhibitor of human CYP1A2. Hence, taking account of CYP1A2 contribution to the metabolism of endogenous substances (steroids), drugs (xanthine derivatives, phenacetin, propranolol, imipramine, phenothiazine neuroleptics, clozapine) and carcinogenic compounds, the inhibition of CYP1A2 by perazine may be of physiological, pharmacological and toxicological importance.

UI MeSH Term Description Entries
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D010464 Perazine A phenothiazine antipsychotic with actions and uses similar to those of CHLORPROMAZINE. Extrapyramidal symptoms may be more common than other side effects. Perazine Dihydrochloride,Perazine Maleate,Perazine Maleate (1:1),Perazine Maleate (1:2),Pernazine,Taxilan,Dihydrochloride, Perazine,Maleate, Perazine
D002110 Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes SMOOTH MUSCLE, stimulates CARDIAC MUSCLE, stimulates DIURESIS, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide PHOSPHODIESTERASES, antagonism of ADENOSINE RECEPTORS, and modulation of intracellular calcium handling. 1,3,7-Trimethylxanthine,Caffedrine,Coffeinum N,Coffeinum Purrum,Dexitac,Durvitan,No Doz,Percoffedrinol N,Percutaféine,Quick-Pep,Vivarin,Quick Pep,QuickPep
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004347 Drug Interactions The action of a drug that may affect the activity, metabolism, or toxicity of another drug. Drug Interaction,Interaction, Drug,Interactions, Drug
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006900 Hydroxylation Placing of a hydroxyl group on a compound in a position where one did not exist before. (Stedman, 26th ed) Hydroxylations
D014150 Antipsychotic Agents Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. Antipsychotic,Antipsychotic Agent,Antipsychotic Drug,Antipsychotic Medication,Major Tranquilizer,Neuroleptic,Neuroleptic Agent,Neuroleptic Drug,Neuroleptics,Tranquilizing Agents, Major,Antipsychotic Drugs,Antipsychotic Effect,Antipsychotic Effects,Antipsychotics,Major Tranquilizers,Neuroleptic Agents,Neuroleptic Drugs,Tranquillizing Agents, Major,Agent, Antipsychotic,Agent, Neuroleptic,Drug, Antipsychotic,Drug, Neuroleptic,Effect, Antipsychotic,Major Tranquilizing Agents,Major Tranquillizing Agents,Medication, Antipsychotic,Tranquilizer, Major
D019388 Cytochrome P-450 CYP1A2 A cytochrome P450 enzyme subtype that has specificity for relatively planar heteroaromatic small molecules, such as CAFFEINE and ACETAMINOPHEN. CYP1A2,Phenacetin O-Dealkylase,CYP 1A2,Caffeine Demethylase,Cytochrome P-450 LM(4),Cytochrome P-450 LM4,Cytochrome P-450d,Cytochrome P450 1A2,CYP1A2, Cytochrome P-450,Cytochrome P 450 CYP1A2,Cytochrome P 450 LM4,Cytochrome P 450d,Demethylase, Caffeine,O-Dealkylase, Phenacetin,P-450 LM4, Cytochrome,Phenacetin O Dealkylase

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