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Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes.

Tamoxifen is the major therapeutic agent for the treatment of hormone-dependent breast cancer. Tamoxifen treatment appears to be associated with an increased incidence of endometrial carcinoma in humans and hepatocellular carcinoma in rats. These carcinogenic effects of tamoxifen might be induced by the formation of a tamoxifen reactive intermediate that binds covalently to macromolecules. Liver microsomal cytochrome P450s (CYPs) catalyze the metabolism of tamoxifen, forming a reactive intermediate that binds irreversibly to microsomal proteins, primarily to a 54 kDa protein (Mani, C. and Kupf

Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity.

Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAP-induced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadmi

Voriconazole and fluconazole increase the exposure to oral diazepam.

OBJECTIVE: We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam. METHODS: Twelve healthy volunteers took 5 mg of oral diazepam in a randomised order on three study sessions: without pretreatment, after oral voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after oral fluconazole 400 mg on the first day and 200 mg on the second day. Plasma concentrations of diazepam and N-desmethyldiazepam were determined for up to 48 h. Pharmacodynamic variables were measured for 12 h. RESULTS: In the voric

Observations on vitamin K deficiency in the fetus and newborn: has nature made a mistake?

The microsomal mixed function oxidase system metabolizes xenobiotics (Phase I) to products that, if not activated and conjugated for excretion (Phase II), are capable of forming conjugates with cellular macromolecules, including DNA, resulting in toxic, mutagenic, or carcinogenic events. Benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon, is a model carcinogen for this system. Vitamin K1 (phylloquinone) is a regulator of BP metabolism. These studies demonstrate that K1 is capable of increasing Phase I metabolism and decreasing glutathione transferase activity (Phase II) in chick embryo liv

Genetic contribution to variable human CYP3A-mediated metabolism.

The human CYP3A subfamily plays a dominant role in the metabolic elimination of more drugs than any other biotransformation enzyme. CYP3A enzyme is localized in the liver and small intestine and thus contributes to first-pass and systemic metabolism. CYP3A expression varies as much as 40-fold in liver and small intestine donor tissues. CYP3A-dependent in vivo drug clearance appears to be unimodally distributed which suggests multi-genic or complex gene-environment causes of variability. Interindividual differences in enzyme expression may be due to several factors including: variable homeostat…

Фармакомикробиомика: От взаимодействия хост-микробиома-наркотики к клиническому переводу в докторскую медицину.

Заметная межиндивидуальная изменчивость реакции на наркотики по-прежнему является серьезной проблемой в области клинической фармакологии и не может быть в полной мере объяснена только генетикой принимающей страны. Растущие данные свидетельствуют о том, что кишечная микробиота является дополнительным фактором, определяющим эффективность и токсичность наркотиков посредством двустороннего взаимодействия с фармакологической терапией. Это признание привело к появлению фармакомикробиомики - области, которая изучает, как микробные сообщества влияют на утилизацию наркотиков и реагирование на них, и ка

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… As early as 1937, intestinal microorganisms were shown to mediate the biotransformation of prontosil into its active sulfonamide form, thereby demonstrating that microbial metabolism could be essential for drug efficacy. … Representative examples of microbiome-mediated drug biotransformation, including the underlying mechanisms and clinical implications, are summarised in Table 1 . …

Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors' late adverse events, including secondary malignant neoplasms (SMNs), car

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… Indeed, one of the common approaches in pharmacogenomic (PGx) studies (i.e., studies carried to investigate genetic compartments in pharmacological responses) is to explore genes affecting the biotransformation of the drug(s) of interest. … Under this assumption, Visscher and coworkers explored variations in 220 genes involved in anthracyclines’ biotransformation. …

β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties.

Natural bicyclic sesquiterpenes, β-caryophyllene (BCP) and β-caryophyllene oxide (BCPO), are present in a large number of plants worldwide. Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells. Nevertheless, their antineoplastic effects have hardly been investigated in vivo. In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells. The mechanisms underlying the anticancer activities of these sesquiterpenes are poorly described. BCP is a phytocannabinoid wit

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… While BCP metabolic pathway was investigated in rabbits, there is some information on BCPO biotransformation. … Takemoto . 1986 Terpenoid biotransformation in mammals IV Biotransformation of (+)‐longifolene,(‐)‐caryophyllene,(‐)‐caryophyllene oxide,(‐)‐cyclocolorenone,(+)‐nootkatone,(‐)‐elemol,(‐)‐abietic acid and (+)‐dehydroabietic acid in rabbits . …

In vitro inhibition of methadone and oxycodone cytochrome P450-dependent metabolism: reversible inhibition by H2-receptor agonists and proton-pump inhibitors.

In vitro inhibition of oxycodone metabolism to noroxycodone and oxymorphone and R- and S-methadone metabolism to R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was measured for four H2-receptor antagonists and five proton-pump inhibitors (PPIs) using human liver microsomes (HLM) and cDNA-expressed human cytochrome P450s (rCYPs). Inhibitors were first incubated with HLM at three concentrations with and without preincubation of inhibitor, enzyme source and reducing equivalents to also screen for time-dependent inhibition (TDI). Cimetidine and famotidine (10-1,000 µM) inhibited

Pyrrolidinediones reduce the toxicity of thiazolidinediones and modify their anti-diabetic and anti-cancer properties.

Thiazolidinediones have been established as a drug class of significant importance in the treatment of Type II diabetes mellitus and have more recently displayed emergent potential as anti-cancer agents. However, their toxicity has hampered clinical development and usage in both therapeutic areas. Studies to date have implicated that the thiazolidinedione ring is responsible for the generation of reactive metabolites after metabolism. As an attempt to improve their safety profiles, we considered the bioisosteric replacement of the thiazolidinedione ring with a chemically conserved pyrrolidined

Alpha1-AR-mediated activation of NKCC in rat cardiomyocytes involves ERK-dependent phosphorylation of the cotransporter.

We studied molecular and functional characteristics as well as hormonal regulation of the Na-K-2Cl cotransporter (NKCC) in the isolated rat heart and cardiomyocytes. NKCC activity was measured as bumetanide-sensitive (86)Rb(+) influx in isolated perfused rat hearts and isolated cardiomyocytes. Stimulation of alpha(1)-adrenoceptors (AR) by phenylephrine (30 microM) increased (86)Rb(+) influx. The NKCC inhibitor bumetanide (50 microM) reduced the response to phenylephrine by 45 +/- 13% (n = 12, P < 0.01). PD-98059 (10 microM), an inhibitor of the activation of the mitogen-activated protein kinas

Cigarette smoke induces direct DNA damage in the human B-lymphoid cell line Raji.

Human lymphoid cells (Raji) were exposed to water-soluble compounds from cigarette smoke (CS) generated in a smoking machine. DNA damage, as detected by alkaline single-cell microelectrophoresis (COMET assay), was induced in a time- and concentration-dependent manner in the cells. Most of the rapidly induced DNA damage was attributable to direct-acting compounds since cytochrome P450-related metabolic activities (ethoxy- and pentoxyresorufin-O-deethylases and coumarin-7-hydroxylase) were absent or very low. In addition, induction of DNA damage could be inhibited only slightly by beta-naphthofl

Individuality in cytochrome P450 expression and its association with the nephrotoxic and carcinogenic effects of chemicals.

The susceptibility of a tissue to the toxic and/or carcinogenic effects of chemicals is determined by a variety of factors, which include their rate of metabolic activation by the cytochrome P450-dependent monooxygenases. Individual differences in the levels of cytochrome P450 expression would be expected, and are known, to give rise to profound differences in toxicological response. Such effects are almost best exemplified by the sex differences observed in the toxic effects of a variety of nephrotoxins and carcinogens. In recent work, we have shown that in species such as the mouse and rat a

Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid.

Endemic (Balkan) nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation, aristolochic acid reacts with genomic DNA to form aristolactam-DNA adducts that generate a unique TP53 mutational spectrum in the urothelium. The aristolactam-DNA adducts are concentrated in the renal cortex, thus serving as biomarkers of internal exposure to aristolochic acid. Here, we present mole

Artificial Intelligence and Machine Learning Technology Driven Modern Drug Discovery and Development.

The discovery and advances of medicines may be considered as the ultimate relevant translational science effort that adds to human invulnerability and happiness. But advancing a fresh medication is a quite convoluted, costly, and protracted operation, normally costing USD ~2.6 billion and consuming a mean time span of 12 years. Methods to cut back expenditure and hasten new drug discovery have prompted an arduous and compelling brainstorming exercise in the pharmaceutical industry. The engagement of Artificial Intelligence (AI), including the deep-learning (DL) component in particular, has bee

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… Foretelling the location of biotransformation with great precision can facilitate the structural refinement for assuring the metabolic endurance of the moiety. … Moreover, the “XenoSite”scheme also employs a neural network trained upon a vast database of UGT biotransformation to foretell UGT loci of the molecule biotransformation [ 183 ]. …

Recurrent headache as the main symptom of acquired cerebral toxoplasmosis in nonhuman immunodeficiency virus-infected subjects with no lymphadenopathy: the parasite may be responsible for the neurogenic inflammation postulated as a cause of different types of headaches.

Headache and/or migraine, a common problem in pediatrics and internal medicine, affect about 5% to 10% children and adolescents, and nearly … laboratory data result at least in part from interference of these factors with dietary tryptophan biotransformation pathways. Several of these agents caused headache attacks through enhancing NO production via the conversion of arginine to citrulline and NO by the inducible nitric oxide synthase enzyme, which results in the high-output pathway of NO synthesis. Th …

Effects of aripiprazole and its active metabolite dehydroaripiprazole on the activities of drug efflux transporters expressed both in the intestine and at the blood-brain barrier.

The inhibition potencies of aripiprazole and its active metabolite, dehydroaripiprazole, on the activities of human multidrug resistance protein 1 (MDR1/ABCB1; P-glycoprotein), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4), that are drug efflux transporters expressed both in the intestine and at the blood-brain barrier (BBB), were investigated. Aripiprazole and dehydroapripiprazole showed relatively strong inhibitory effects on human MDR1 with IC(50) values of 1.2 and 1.3 µm in human MDR1-transfected Mardin-Darby canine kidney (MDCKII-

High-throughput cytochrome P450 (CYP) inhibition screening via a cassette probe-dosing strategy. VI. Simultaneous evaluation of inhibition potential of drugs on human hepatic isozymes CYP2A6, 3A4, 2C9, 2D6 and 2E1.

The inhibition potential of drugs towards five major human hepatic cytochrome P450 (CYP) isozymes (CYP2A6, 3A4, 2C9, 2D6, and 2E1) was investigated via cassette dosing of the five probe substrates (coumarin, midazolam, tolbutamide, dextromethorphan, and chlorzoxazone) in human liver microsomes using a 96-well plate format. After microsomal incubations had been terminated with formic acid, the five marker metabolites (7-hydroxycoumarin, 1'-hydroxymidazolam, 4-hydroxytolbutamide, dextrorphan, and 6-hydroxychlorzoxazone) were simultaneously quantified using direct injection/online guard cartridge

Modafinil : A Review of its Pharmacology and Clinical Efficacy in the Management of Narcolepsy.

SYNOPSIS: Modafinil promotes wakefulness through an as yet unknown mechanism of action. It significantly increases daytime sleep latency and reduces excessive daytime sleepiness (EDS) compared with placebo in patients with narcolepsy. However, the drug does not suppress cataplexy. Although direct comparative data are lacking, modafinil offers advantages over amphetamines and methylphenidate in patients with narcolepsy because of its lack of rebound phenomena after treatment withdrawal and its low abuse potential. Clinical trials have shown modafinil to be well tolerated in patients with narcol

[Etravirine drug interactions].

Etravirine (ETR) belongs to the family of non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs), with antiviral activity in patients with resistance to first-generation NNRTIs. The drug interactions caused by ETR are due to its dual effect on the CYP450 system. ETR acts as an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. This drug shows few clinically significant drug interactions, the most important of which involve the unboosted protease inhibitors, the NNRTIs efavirenz and nevirapine, full-dose ritonavir and tipranavir/ritonavir. Interaction with fosamprenavir/ritonavir