Salidroside (SAL) is the active ingredient of the traditional adaptogenic herb Rhodiola rosea. Cytochromes P450 (P450), crucial enzymes in drug metabolism, are central to understanding drug–herb interactions. This study investigates the impact of SAL on the metabolic activity of selected P450 in both rat and human systems. Wistar rats were administered intragastrically with SAL 5, 15, or 45 mg/kg/day for seven days. The metabolic activity of CYP1A2, CYP2C6, CYP2D, and CYP3A was measured in rat liver microsomes (RLMs). Amounts and gene expressions of CYP1A2 and CYP2C6 were assessed in RLMs using Western blot and two-step qRT-PCR. rPXR, hPXR, and CAR3 gene reporter assays were conducted. The in vitro inhibitory studies of SAL in both drug-naïve rat and human liver microsomes were performed. Interactions between SAL and human P450 were also studied by in silico methods. SAL at the dose of 5 mg/kg/day slightly increased the specific activity of the P450 studied. However, SAL did not change either the P450 protein levels or the expression of the corresponding genes in rat liver. It also did not cause direct inhibition of rat and human P450 in liver microsomes in vitro. Molecular docking with human P450 confirmed these findings. Moreover, SAL inhibited the agonist-mediated induction of both rat and human PXR. Based on our findings, SAL is unlikely to pose a significant risk of P450-mediated drug-herb interactions and rather preserves the constitutional CYP3A metabolic activity via interaction with PXR. Not applicable.

Metformin is a widely used drug with a relatively good efficacy in diabetes treatment, a good safety profile, and the potential for use in other indications. The variability in the individual responses to metformin therapy is partially determined by genetic factors. This narrative review aimed to summarize information on single nucleotide variant (SNVs) in genes for transporter proteins associated with metformin pharmacokinetics and pharmacodynamics and/or the occurrence of adverse effects. The Pharmacogenomics Knowledge Base (PharmGKB) and Web of Science databases were searched for metformin-associated gene variants that could affect its action. Seven transporter genes with twelve SNVs common in the European population were identified in the PharmGKB database, namely SNVs in genes SLC22A1 (OCT1), SLC22A2 (OCT2), SLC22A3 (OCT3), SLC22A4 (OCTN1), SLC47A1 (MATE1), SLC47A2 (MATE2-K), and SLC2A2 (GLUT2); it is worth noting that GLUT2 is not metformin transported but a glucose transporter and as such, it can also influence metformin action. Based on 63 retrieved studies, the association of individual SNVs with metformin effectiveness and adverse effects is discussed. In view of the high variability of study designs, populations, and reporting patterns, we also propose a framework for the design and reporting of metformin-associated pharmacogenetic studies, suggesting also that determining a complete set of these SNVs could help in comprehensive understanding of genetically conditioned individual responsiveness to metformin therapy, thus opening the path to maximizing the utilization of its positive effects while minimizing the risk of adverse effects. In addition, given the large variability in designs among studies, we also propose a framework for future studies on SNVs in metformin action-associated transporters that could improve comparability of future studies.

The use of cannabinoids has a history spanning thousands of years, and their pharmacological and toxicological properties, particularly those of THC and CBD, are well-documented. However, their potential to induce drug-drug interactions remains underexplored. This review aims to provide a comprehensive perspective by contextualizing the historical and pharmacological significance of cannabinoids while focusing on their capacity to modulate the metabolic activity of cytochrome P450 isoforms relevant to drug metabolism. Additionally, we look at the impact of cannabinoids in neuronal circuits impacting the hypothalamic-pituitary hormonal axis, such as the locus coeruleus and raphe nuclei and their possible consequences on the cytochrome P450 system. Recognising potential interactions between cannabinoids and other drugs could enhance understanding of their pharmacological effects, improve the efficacy and safety profiles of cannabinoid-based therapies, and encourage further exploration into this under-researched area of psychopharmacology, with implications for both preclinical research and clinical practice.

A series of eighteen new 2-trifluoromethylcinnamanilides (1a-r) were synthesized by microwave synthesis and investigated for their antimycobacterial and antimalarial activities, along with the complementary (2E)-3-[3-(trifluoromethyl)phenyl]-N-arylprop-2-enanilides (2a-r) and (2E)-3-[4-(trifluoromethyl)phenyl]-N-arylprop-2-enanilides (3a-r) prepared earlier. All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102. The most active compounds against M. smegmatis (MIC values in the range of 1.17-11.1 µM, more effective than rifampicin) were anilides substituted by 3,5-CF3 (1q, 2q, 3q), 4-OCF3 (1k), and 4-CF3 (1j, 2j). The most effective agents against P. falciparum (IC50 values in the range of 0.32-4.5 µM, comparable to chloroquine) were anilides substituted by 3,5-CF3 (1q, 2q, 3q), 2-Br-4-OCF3 (1r), 4-CF3 (1j, 3j), 4-F (2d), 4-Cl (2g), 2-Cl (1e, 2e). A preliminary in vitro cytotoxicity screening was assessed using human leukemic cell lines and human dermal fibroblasts, revealing the toxic effect of 3,5-CF3 substituted anilides. On the other hand, the other investigated agents showed insignificant cytotoxic effects. Stability assays using rat liver microsomes demonstrated that compounds 1r (R = 2-Br-4-OCF3) and 1q (R = 3,5-CF3) are neither metabolized nor affect cytochrome P450 metabolizing capacity in vitro. Furthermore, complex in silico studies were performed - a combined approach (docking/MD simulations/QTAIM calculations) helped to define the molecular interactions that were applied during the binding of active agents and the subsequent inhibition of their molecular targets - InhA (activity against M. smegmatis) and arginase (activity against P. falciparum). In conclusion, promising active agents with dual antimycobacterial and antimalarial effects were identified.

Both denosumab (DMB) and bisphosphonates (BPs), antiresorptive drugs (ARDs) used for the treatment of osteoporosis and oncological disorders, are known for their potential to cause medication-related osteonecrosis of the jaws (MRONJ). Besides ARDs, statins were recently associated with MRONJ development, especially in patients taking higher doses of statins for a longer period of time. Here, we report a case of a female patient with osteoporosis using statins and treated with alendronate for 3 years who rapidly developed MRONJ stage III after only a single low dose of DMB. After partial maxillectomy complete healing was observed without any recurrence. We performed a literature review of cases with MRONJ triggered by a single low dose of DMB, with or without previous application of other ARDs. Only six similar cases of patients who developed MRONJ after a single low dose of DMB following previous BP therapy have been reported so far. Besides these, literature reports one patient who developed MRONJ after a single dose of DMB following romosozumab treatment and five cases developing MRONJ after a single dose of DMB even without any previous ARD treatment. We suggest that before DMB therapy is initiated, all factors predisposing to MRONJ development should be considered.

Abstract Both denosumab (DNO) and bisphosphonates (BP), antiresorptive drugs (ARDs) used for the treatment of osteoporosis and oncological disorders, are known for their potential to cause medication-related osteonecrosis of the jaws (MRONJ). Besides ARDs, statins were recently associated with MRONJ development, especially in patients taking higher doses of statins for a longer period of time. Here, we report a case of a woman with osteoporosis who rapidly developed MRONJ stage III after only a single low dose of DNO. The patient was taking statins (rosuvastatin) for 7 years and had also been on BP (alendronate) for 4 years previously but this treatment was discontinued for approximately 1.5 years before MRONJ development. We performed a literature review of cases with MRONJ triggered by a single low dose of DNO and of cases with statin-induced MRONJ in patients not using ARD. Because the MRONJ development after a single low dose of DNO is rare, only eleven cases were previously described. We suggest that (i) in some patients, long-term use of statins and BP may lead to a higher susceptibility of MRONJ development after DNO exposure and (ii) that all predisposing factors to MRONJ development including the necessity of any dental procedures should be considered before DNO therapy is initiated.

To this date, there are no recommendations for personalized stress ulcer prophylaxis (SUP) in critical care that would take the patient's individual genetic predispositions into account. Of drugs used for this purpose, proton pump inhibitors (PPIs) are the first-choice drugs in intensive care unit patients. The degradation of proton pump inhibitors is mediated by cytochrome P450 (CYP) enzymes; in particular, CYP2C19 and, to a lesser extent, CYP3A4 are involved. Expression and metabolic activity of, namely in, CYP2C19 is significantly affected by single nucleotide polymorphisms, the drug metabolization rate varies greatly from ultrarapid to poor and likely influences the optimal dosage. As these CYP2C19 predictive phenotypes via CYP2C19 haplogenotypes (rs12248560/rs4244285) can be relatively easily determined using the current standard equipment of hospital laboratories, we prepared a set of recommendations for personalized PPI-based stress ulcer prophylaxis taking into account the patient's CYP2C19 predictive phenotype determined in this way. These recommendations are valid, in particular, for European, American and African populations, because these populations have the high representations of the CYP2C19*17 allele associated with the overexpression of the CYP2C19 gene and ultrarapid degradation of PPIs. We propose the CYP2C19 gene profiling as a tool for personalized SUP with PPI in critically ill patients.

Tetracycline compounds present a broad spectrum of antibiotics widely used in medicine. Since their discovery they have been used in the treatment of human diseases as well as in veterinary applications. However, their overuse in food-producing animals may express an adverse effect on human health and even induce selective resistance. Selected antibiotics from the class of tetracyclines have been analyzed using liquid chromatography with fluorescence detection (LC-FLU) and LC with mass spectrometric detection (LC-MS) on a core-shell C18 column. As majority systems nowadays rely on reversed-phase columns with water being the main component of the mobile phase, a simple replacement of H 2 O with D 2 O in the mobile phase enhanced the sensitivity for selected compounds by 10–200%. MS was used to unambiguously identify the separated compounds and to locate the labile hydrogen sites. Another way to increase the fluorescence intensity lied in production of complex compounds of the tetracycline molecules and Mg 2+ ions. Such simple yet effective approaches improved limits of detection and sensitivity and may be selectively exploited (on demand) in the LC-FLU analysis of these compounds.

Uvod: Alkaloid harman je s-karbolin vyskytujici se v rostlinach s psychotropnim ucinkem Passiflora incarnata (Passifloraceae) a Banisteriopsis caapi (Malpighiaceae). Jedna se o farmaceuticky významne rostliny. P. incarnata je hojně použivana pro svůj sedativni a anxiolytický ucinek, B. caapi tvoři zakladni složku tradicniho napoje ayahuasca s halucinogennim a potencialně antidepresivnim ucinkem. Latka je take přitomna v kavě a v tabakovem kouři, kde je ji připisovan inhibicni efekt na MAO A. Cilem teto studie bylo ověřeni vlivu harmanu na nejvýznamnějsi formy cytochromu P450 in vivo. Metody: Byla provedena preklinicka studie, při niž byl potkanům intragastricky aplikovan harman ve 3 davkach (25, 40 a 64 mg/kg) po dobu 8 dnů. Po odběru jater byla izolovana mikrosomalni frakce a byla stanovena změna absolutni metabolicke aktivity vybraných forem CYP za použiti CYP specifických substratů (fenacetin, diklofenak, testosteron, dextrometorfan). Metabolity byly kvantifikovany pomoci HPLC ve spojeni s fluorescencni detekci nebo detekci diodovým polem. Výsledky byly vyhodnoceny pomoci SW Statistica. Výsledky: Bylo zjistěno, že harman inhibuje absolutni metabolickou aktivitu potkannich cytochromů CYP2D2, CYP2A1, CYP2C11 a CYP3A1, v některých připadech na davce zavisle. Vliv na CYP1A2 a CYP2C6 prokazan nebyl. Diskuse: Vzhledem k oblibě volně prodejných sedativ a anxiolytik obsahujicich rostlinu Passiflora incarnata je prokazani interakcniho potencialu harmanu s cytochromy P450 významne nejen pro klinickou psychiatrickou praxi, ale obecně pro veskerou medikaci.

Salidrosid je glykosid patřici mezi sekundarni metabolity Rhodiola rosea. Standardizovaný extrakt Rhodiola rosea vykazal adaptogenni, stimulacni, anxiolyticke a antidepresivni ucinky u zviřecich modelů. Byl take prokazan anxiolytický a antidepresivni efekt roztoku salidrosidu, který může být ovlivněn jeho antiflogistickými a neuromodulacnimi vlastnostmi v CNS. Cilem teto prace bylo hodnoceni vlivu salidrosidu na vybrane enzymy cytochromu P450 (CYP) po přime interakci in vitro. Byla hodnocena změna metabolicke aktivity vybraných enzymů CYP in vitro metodou ko-inkubace jaterni mikrosomalni frakce, CYP-specifických substratů a vzrůstajicich koncentraci salidrosidu. Mikrosomy byly inkubovany za definovaných podminek s vybraným substratem (diklofenak (CYP2C6), dextrometorfan (CYP2D1/2), fenacetin (CYP1A2), testosteron (CYP2A, CYP3A, CYP2C, CYP2B)), s roztoky salidrosidu (0,1 uM, 1 uM, 10 uM nebo 100 uM) nebo s roztokem vehikula. Množstvi metabolitů bylo vyhodnoceno pomoci HPLC a fluorescencni/DAD detekce. Při in vitro inkubacich směsi potkannich mikrozomů a salidrosidu o koncentracich 0,1 uM, 1 uM, 10 uM ani 100 uM nebyla prokazana signifikantni změna metabolicke aktivity ve srovnani s kontrolnimi vzorky. Změna metabolicke aktivity nebyla zaznamenana ani u preinkubovaných vzorků. In vitro inkubace salidrosidu neprokazaly změnu metabolicke aktivity u žadneho z testovaných enzymů CYP (CYP2C6, CYP2D1/2, CYP1A2, CYP2A, CYP3A, CYP2C, CYP2B). V nasledne studii bude zkouman vliv salidrosidu na metabolickou aktivitu CYP po subchronicke intragastricke aplikaci in vivo. Tento pokus by mohl bliže objasnit dlouhodobe ucinky salidrosidu na enzymy cytochromu P450 u potkana.

BACKGROUND:Lycopene as a naturally occurring carotenoid is a common part of the human diet. Several beneficial properties of lycopene have been identified, with the most studied being anti-cancer and antioxidant activity. However, no evidence of possible drug-drug or drug-food supplement interactions has been found.METHODS:We studied the in vivo effect of lycopene on the selected rat liver cytochromes P450 (CYPs): CYP1A2, CYP2B, CYP2C11, CYP2C6, CYP2D, and CYP3A. Lycopene was administered to rats intragastrically at doses of 4, 20, and 100 mg/kg/day for 10 consecutive days. Total protein content, P450 Content, and metabolic activity of selected CYPs were evaluated in the rat liver microsomal fraction.RESULTS:Increased CYP2B, CYP2D, and CYP3A metabolic activities were observed in animals treated with the lycopene dose of 100 mg/kg/day. The content of CYP3A1 protein was increased by the dose of 100 mg/kg/day and CYP3A2 protein was increased by all administered doses of lycopene.CONCLUSION:The results of our study indicate that lycopene increased the metabolic activity of enzymes that are orthologues to the most clinically important human enzymes involved in xenobiotic metabolism. The risk of pharmacokinetic interactions between lycopene dietary supplements and co-administered drugs should be evaluated.

A simple and sensitive liquid chromatography method with absorbance or mass spectrometry detection was developed and validated for the determination of lansoprazole, lansoprazole sulfone, and 5-hydroxylansorpazole in human serum with omeprazole as an internal standard. Analytes were, after an extraction step with a mixture of isopropyl alcohol: dichloromethane (2:8, v/v), separated in a gradient elution (acetonitrile: 20 mM ammonium formate) and detected at 280 and 300 nm or by monitoring selective reactions in a triple quadrupole mass analyzer. The limits of detection were, for all analytes, below 2 ng/mL and 3 pg/mL in the LC UV and LC MS method, respectively. The combined linear dynamic range exceeded 5 orders of magnitude. The method was successfully applied in the assessment of CYP2C19 and CYP3A4 metabolic phenotypes in ST-elevated myocardial infarction patients receiving novel anticoagulant treatment.

The endocannabinoid system is important for many physiologic and pathologic processes, but its role in the regulation of liver cytochromes P450 (P450s) remains unknown. We studied the influence of the endocannabinoid oleamide on rat and human liver P450s. Oleamide was administered intraperitoneally to rats at doses of 0.1, 1, and 10 mg/kg per day for 7 days. The content and activity of key P450s were evaluated in rat liver microsomes. Moreover, interactions with nuclear receptors regulating P450 genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in in vitro P450 inhibition assays. Decreased protein levels and metabolic activities of CYP1A2, CYP2B, and CYP2C11, along with a drop in metabolic activity of CYP2D2, were observed in animals treated with oleamide (10 mg/kg per day). The activities of CYP2C6, CYP2A, and CYP3A and the levels of hormones were not altered. In vitro, oleamide exhibited a weak inhibition of rat CYP1A2, CYP2D2, and CYP2C6. The activities of rat CYP2A, CYP2B, CYP2C11, and CYP3A and human CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were not altered. Oleamide did not interact with human pregnane X, constitutive androstane, or aryl hydrocarbon receptors in reporter gene experiments and did not regulate their target P450 genes in primary human hepatocytes. Our results indicate that oleamide caused the downregulation of some rat liver P450s, and hormones are not mediators of this effect. In vitro oleamide inhibits mainly rat CYP2C6 and is neither an agonist nor antagonist of major human nuclear receptors involved in the regulation of xenobiotic metabolism.

(-)-Linalool is the major floral scent occurring mainly in families Lamiaceae, Lauraceae and Rutaceae and is the main active compound of lavender oil. The purpose of this study was to reveal the influence of subchronic systemic treatment with (-)-linalool on the metabolic activity of CYP2A, 2B, 2C6, 2C11 and 3A in rat liver microsomes (RLM). The second aim was to reveal possible inhibitory effect of (-)-linalool on CYP2C6 in vitro. Wistar albino male rats were treated with (-)-linalool intragastrically at the doses of 40, 120, and 360 mg/kg/day for 13 days. Treatment with (-)-linalool at the dose of 360 mg/kg increased the metabolic activity of CYP2A assessed with testosterone as a probe substrate. (-)-Linalool showed weak competitive inhibition of CYP2C6 in rat liver microsomes, with IC(50) of 84 microM with use of diclofenac as a probe substrate.

This review summarizes the importance of bile acids (BA) as important regulators of various homeostatic mechanisms with detailed focus on cytochrome P450 (CYP) enzymes. In the first part, synthesis, metabolism and circulation of BA is summarized and BA are reviewed as physiological ligands of nuclear receptors which regulate transcription of genes involved in their metabolism, transport and excretion. Notably, PXR, FXR and VDR are the most important nuclear receptors through which BA regulate transcription of CYP genes involved in the metabolism of both BA and xenobiotics. Therapeutic use of BA and their derivatives is also briefly reviewed. The physiological role of BA interaction with nuclear receptors is basically to decrease production of toxic non-polar BA and increase their metabolic turnover towards polar BA and thus decrease their toxicity. By this, the activity of some drug-metabolizing CYPs is also influenced what could have clinically relevant consequences in cholestatic diseases or during the treatment with BA or their derivatives.

Skripta jsou urcena studentům bakalařských oborů pro studium farmakologie na Farmakologickem ustavu na Lekařske fakultě Masarykovy univerzity. Ucebni text se zabýva obecnými principy vzajemneho působeni organismu a lecivých latek a specialni farmakologii v rozsahu nezbytnem pro jednotlive bakalařske studijni obory. Obecna farmakologie je doplněna kapitolami shrnujicimi zakladni charakteristiky životniho cyklu leciv a aktualni legislativni normy zavazne pro předepisovani, uchovavani a vydavani lecivých připravků.