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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
INH is a weak or moderate inhibitor of some CYP isoforms in vitro (CYP1A2, CYP2A6, CYP3A4, and CYP2C19)26 though few confirmed clinically relevant DDIs consistent with these findings have been reported. CYP2B6 slow metabolizers may have clinically important rises in efavirenz plasma concentrations due to INH inhibition of CYP2A6, which is a key accessory metabolic route for these individuals.27 Drugs that are substrates for CYP3A4 or CYP2C19 including anticonvulsants, coumarins, citalopram, diazepam, and theophylline may have reduced clearance and higher-plasma concentrations. There may also be potential for enhanced hepatotoxicity of paracetamol through undefined mechanisms.
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Kandace L. Amend, Ji-Yeob Choi, Christine B. Ambrosone
The human cytochrome P450 CYP2B6 gene is involved in the metabolic activation of a number of clinically important chemotherapeutic drugs for breast cancer, including CP (10,11) as well as the antioestrogen TAM (12). Several single nucleotide polymorphisms (SNPs) in CYP2B6 have been described, some having functional significance (13) and affecting the pharmacokinetic parameters of CP. In cell culture, enzymatic activities in microsomes from COS-1 cells expressing a K262R amino acid substitution (CYP2B6*4, CYP2B6*6, and CYP2B6*7) showed increased values for Vmax and Vmax/Km compared with that of the wild type (CYP2B6*1) (14), while a second study reported that the amino acid substitution Q172H resulting from the CYP2B6*6 allele enhanced 7-ethoxycoumarin O-deethylase activity (15). A study by Lang et al. (2001) identified a total of nine SNPs by sequencing DNA from 35 subjects and reported extensive variability in the expression and activity of CYP2B6, where CYP2B6 expression was significantly reduced in carriers of the R487T, Q172H, and K262R polymorphisms (16). Ethnic variation in allelic variants and CYP2B6 expression has been also been observed (17,18).
Pharmacological Management of Parkinson’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Newman Osafo, Samuel Obeng, David D. Obiri, Oduro K. Yeboah, Leslie B. Essel
In addition to N-demethylation, orphenadrine is also metabolized via deamination and conjugation with 60% excretion via the renal system within 72 h. Only 8% of the drug is excreted unchaged (Guo et al., 1997). The drug interacts with CYP2B6 and CYP2D6, and cause up to 45–57% and 80–90% reduction in microsomal enzymes, respectively (Ellison, 1972). CYP1A2, CYP2A6, CYP3A4, and CYP2C19 marker activities are however decreased to a lesser extent. Only about a percentage of biperiden is excreted unmetabolized in urine with a chunk of the drug metabolized (Grimaldi et al., 1986).
Cannabinoids and drug metabolizing enzymes: potential for drug-drug interactions and implications for drug safety and efficacy
Published in Expert Review of Clinical Pharmacology, 2022
Keti Bardhi, Shelby Coates, Christy J.W. Watson, Philip Lazarus
There are 10 major CYP enzymes involved in xenobiotic drug metabolism: CYP3A4, CYP2A6, CYP2D6, CYP2C8, CYP2C9, CYP1A2, CYP2C19, CYP2E1, CYP2B6, and CYP2A6, and these account for 70–80% of all drug metabolism [143]. CYP-mediated metabolism is highly susceptible to DDI and is thought to account for much of the variability in drug response [143,144]. As the risk for DDI is high for the CYP family of enzymes, the FDA has proposed a set of guidelines for the study of the interactions between CYPs and potential perpetrator drugs [145]. This guidance focuses both on the inhibition and induction of CYP enzymes in an in vitro system, and also tasks researchers with the characterization of the DDI potential of metabolites, if they exceed parent drug exposure by 1.25-fold [145]. As several THC and CBD metabolites exceed parent drug exposure by ≥ 1.25-fold, this becomes particularly important when considering the potential inhibitory effects of cannabis. The FDA recommends not only in vitro DDI studies but also static (mechanistic static modeling) and dynamic (physiologically based pharmacokinetic – PBPK) modeling when preliminary data and physiological conditions suggests a potential interaction [145].
Newly identified tree shrew cytochrome P450 2B6 (CYP2B6) and pig CYP2B6b are functional drug-metabolising enzymes
Published in Xenobiotica, 2022
Yasuhiro Uno, Genki Ushirozako, Shotaro Uehara, Norie Murayama, Yuki Fujiki, Hiroaki Kawaguchi, Kyoko Tsukiyama-Kohara, Hiroshi Yamazaki
The cytochromes P450 (P450s or CYPs) constitute a family of haem–thiolate enzymes catalysing the oxidation or reduction reactions of various endogenous and exogenous substrates; in humans, the P450s comprise 57 functional genes and 58 pseudogenes (Nelson et al. 2004). The human CYP2B subfamily contains functional CYP2B6 and pseudogene CYP2B7P, and CYP2B6 constitutes approximately 2–5% of total P450 proteins in human liver (Gervot et al. 1999; Shimada et al. 1999; Lang et al. 2001). Human CYP2B6 metabolises various substrates, including clinically important pharmaceuticals, bupropion, cyclophosphamide, diazepam, efavirenz, and tamoxifen (Lang et al. 2001). Marmoset CYP2B6 and cynomolgus macaque CYP2B6 notably showed unique substrate selectivity; these enzymes do not effectively catalyse efavirenz 8-hydroxylation, unlike human CYP2B6 (Oshio et al. 2019). Human CYP2B6 is also induced by phenobarbital via mechanisms involving nuclear receptors, constitutive androstane receptor, and pregnane X receptor (Wang and Negishi 2003).
DEC1 negatively regulates CYP2B6 expression by binding to the CYP2B6 promoter region ascribed to IL-6-induced downregulation of CYP2B6 expression in HeLa cells
Published in Xenobiotica, 2021
Xiaofei Luan, Yi Zhao, Na Bu, Yue Chen, Nan Chen
Our previous studies have demonstrated that the human DEC1 (differentially expressed in chondrocytes) gene can bind to the CYP3A4 promoter region and inhibit the expression and enzyme activity of CYP3A4 in hepatocytes (Zhao et al. 2012). Here, we focussed on the drug metabolism enzyme CYP2B6, explored the relationship between the DEC1 gene and CYP2B6, and investigated the factors influencing the activity of CYP2B6 from a pharmacogenetics perspective. HeLa cells were chosen as the basic cells and IL-6 (20 ng/mL) was applied to HeLa cells to simulate the inflammatory environment of the tumour in vitro. Our results showed that IL-6 can inhibit the expression of CYP2B6 and time-dependently promote the expression of DEC1 in HeLa cells, whereas DEC1 can regulate the expression of CYP2B6. The luciferase reporter assay and ChIP assay showed that DEC1 inhibited the expression of CYP2B6 by binding to the CYP2B6 promoter. The results of ELISA showed that DEC1/CYP2B6 promoted the secretion of IL-6 in HeLa cells, thus playing a reverse regulatory role. In conclusion, our results suggest that the DEC1/CYP2B6 pathway is closely related to the inflammatory environment of tumours, which can provide a weakly aligned theoretical framework for the study of genes encoding drug metabolising enzymes.