Ondřej Zendulka

Cannabinoids and Cytochrome P450 Interactions

OBJECTIVE This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. METHODS We performed a structured search of bibliographic and drug databases for peer-reviewed literature using focused review questions. RESULTS Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.

The effect of methamphetamine on biotransformation of ethanol:pilot study

Abstract Methamphetamine is one of the most popular recreational drugs in Central Europe and is often combined with ethanol. Various interactions between these two substances have been described including the influence of administered ethanol on biotransformation of methamphetamine. The aim of the present study was to describe the opposite effect - the influence of methamphetamine on biotransformation of ethanol in rats. Methamphetamine was administered for 10 days (10 mg/kg/day) i.p. and ethanol was delivered as an intragastric bolus (2 g/kg) on the10th day of experiment to both methamphetamine administered rats and control animals. The pharmacokinetic experiment on the whole animal was performed and plasma samples were drawn at the 40th, 120th, 210th and 300th minute after ethanol administration. Ethanol plasmatic levels reached significantly lower values in the 40th and 120th interval when compared to controls. Differences were insignificant in the last two intervals. Our results suggest that chronic methamphetamine administration induces ethanol biotransformation. We suppose that this effect is caused by induction of alcohol dehydrogenase metabolic activity or by allosteric interaction of methamphetamine and this enzyme. More studies have to be conducted to confirm or disprove our hypothesis. Metamfetamin je jednou z nejčastěji zneužívaných drog v regionu Střední Evropy a velmi často je jeho užívání kombinováno s požíváním alkoholu. V minulosti byly popsány rozličné interakce mezi těmito dvěma látkami včetně vlivu ethanolu na biotransformaci metamfetaminu. Cíl této práce je přesně opačný, tedy popsat vliv metamfetaminu na biotransformaci etanolu u potkana. Metamfetamin (10 mg/kg/den) byl zvířatům aplikován ve formě i.p. injekcí 10 dní. Ethanol (2 g/kg intragastricky) byl podán kontrolním i metamfetaminem premedikovaným zvířatům společně s poslední dávkou metamfetaminu. Následně byl proveden farmakokinetický experiment na celém zvířeti s odběrem vzorků krve v následujících časových intervalech od aplikace ethanolu: 40, 120, 210 a 300 minut. Hladiny ethanolu v plazmě stanovené metodou plynové chromatografie byly signifikantně nižší u metamfetaminem premedikovaných zvířat než u kontrol ve 40. a 120. minutě experimentu, zatímco v následujících dvou časových intervalech byl rozdíl nesignifikantní. Naše výsledky naznačují, že chronicky aplikovaný metamfetamin zrychluje biotransformaci ethanolu. Domníváme se, že tento efekt je zprostředkován prostřednictvím alkoholdehydrogenázy buď zvýšení genové exprese nebo alosterickou modulací tohoto enzymu vlivem metamfetaminu. K ověření nebo vyvrácení naší hypotézy je nutné provést další studie.

Determination of Caffeine and its Metabolites in Saliva and Urine as a Measure of CYP1A2 Metabolic Activity

Byla vyvinuta nova citliva a robustni RP-HPLC metoda pro stanoveni kofeinu, 1,7 dimethylxanthinu, 1,7-dimethylmocove kyseliny, 5-acetylamino-6-formylamino-3-methyluracilu, 5-acetylamino-6-amino-3-methyluracilu, 1-methylxanthinu a 1-methylumocove kyseliny ve slinach a moci. Metoda slouži ke stanoveni metabolicke aktivity CYP1A2.