Review
Medicine, Research & Experimental
Mohammed G. Maslub, Mahasen A. Radwan, Nur Aizati Athirah Daud, Abubakar Sha'aban
Summary: This article reviews the association between genetic variations in CYP3A4/5 and the response to atorvastatin therapy globally, including its pharmacokinetics and the risk of adverse reactions. It also highlights the need for further studies in the Egyptian population.
EUROPEAN JOURNAL OF MEDICAL RESEARCH
(2023)
Article
Food Science & Technology
Xiaodan Zhang, Qingqing Li, Quan Zhou, Yunxuan Li, Junwei Li, Lehao Jin, Sen Li, Jianping Cai, Gaozhi Chen, Guoxin Hu, Jianchang Qian
Summary: This study evaluated the impact of CYP3A4 gene polymorphism on the metabolism of artemether-lumefantrine and found significant differences in the clearance rate of different genotypes. These findings enhance our understanding of drug metabolism and provide important insights for guiding treatment strategies.
FOOD AND CHEMICAL TOXICOLOGY
(2023)
Review
Pharmacology & Pharmacy
Jung Sun Kim, Sunyoung Shim, Jeong Yee, Kyung Hee Choi, Hye Sun Gwak
Summary: This meta-analysis evaluated the association between CYP3A4*22 polymorphism and the dose-adjusted trough concentration (C-0/D) of Tac in adult kidney transplant patients. The results showed that patients carrying the CYP3A4*22 allele had significantly higher C-0/D of Tac and lower daily dose requirement. Additionally, the presence of CYP3A5*3 polymorphism also greatly impacted Tac blood concentration.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mingming Han, Jianchang Qian, Zhize Ye, Renai Xu, Daoxing Chen, Saili Xie, Jianping Cai, Guoxin Hu
Summary: Genetic polymorphism extensively impacts CYP3A4's enzymatic activity in metabolizing ACA, showing varied capabilities even within the same variants. The inhibitory potency of CYP inhibitor differs among different variants when combined with ACA. The distance between the substrate and the heme iron atom, likely influenced by mutation, plays a crucial role in determining the enzymatic capabilities of CYP3A4.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Article
Neurosciences
Lisa R. Goldberg, Thomas J. Gould
Summary: Nicotine use is a significant public health concern, and genetic factors play a role in adolescent nicotine use and addiction. Further research is needed to understand the impact of genetic variants on nicotine use in both adolescence and adulthood, as well as their long-term consequences.
BRAIN RESEARCH BULLETIN
(2022)
Article
Oncology
Yadira X. Perez-Paramo, Christy J. W. Watson, Gang Chen, Claire E. Thomas, Jennifer Adams-Haduch, Renwei Wang, Chiea Chuen Khor, Woon-Puay Koh, Heather H. Nelson, Jian-Min Yuan, Philip Lazarus
Summary: The study investigated the effects of CYP2A6 deficiency on nicotine metabolism and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolite levels. The results showed significant associations between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, suggesting that different pathways of nicotine metabolism may have an impact on nicotine dependence and smoking behavior.
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
(2023)
Article
Pharmacology & Pharmacy
Yixin Hu, Jianyuan Wu, Bingyu Cheng, Rongli You, Xueyan Yin, Guiying Chen, Ling Yang, Yang Zhang, Luqin Si, Hongliang Jiang, Yongjun Zhang, Jianying Huang, Jiangeng Huang
Summary: Polymorphisms in the SLCO2B1 gene significantly affect the pharmacokinetic variability of ABI and its metabolites under both fasted and fed conditions. High-fat meal intake greatly increases the systemic exposure of ABI and its metabolites. The SLCO2B1 rs1077858 variant has a significant influence on the pharmacokinetic parameters of ABI, while other SLCO2B1 variants prolong the half-life of ABI. Polymorphisms in CYP3A4 and UGT1A4 do not significantly affect the pharmacokinetics of ABI and its metabolites.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Lianne Beunk, Marga Nijenhuis, Bianca Soree, Nienke J. de Boer-Veger, Anne-Marie Buunk, Henk Jan Guchelaar, Elisa J. F. Houwink, Arne Risselada, Gerard A. P. J. M. Rongen, Ron H. N. van Schaik, Jesse J. Swen, Daan Touw, Roos van Westrhenen, Vera H. M. Deneer, Jan van der Weide
Summary: The Dutch Pharmacogenetics Working Group (DPWG) has developed evidence-based guidelines to optimize pharmacotherapy by promoting the implementation of pharmacogenetics in clinical practice. This guideline describes the gene-drug interactions between CYP2D6, CYP3A4, CYP1A2 genes and antipsychotics. The DPWG recommends therapy adjustments based on genotype for certain antipsychotics, such as dose reduction for CYP2D6-predicted poor metabolizers (PMs) and dose increase or alternative drug for ultra-rapid metabolizers (UMs). Limited evidence suggests alternative drug choice or dose reduction for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for other predicted phenotypes.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Pharmacology & Pharmacy
Ahmed El-Boraie, Meghan J. Chenoweth, Jennie G. Pouget, Neal L. Benowitz, Koya Fukunaga, Taisei Mushiroda, Michiaki Kubo, Nicole L. Nollen, Lisa Sanderson Cox, Caryn Lerman, Jo Knight, Rachel F. Tyndale
Summary: The Nicotine Metabolite Ratio (NMR) is influenced by smoking behavior, diseases, and cessation outcomes. Genetic risk scores based on CYP2A6 for European and African populations can accurately reflect metabolizer types and predict the NMR.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Pharmacology & Pharmacy
Michael L. Williams, Prince J. Kannankeril, Joseph H. Breeyear, Todd L. Edwards, Sara L. Van Driest, Leena Choi
Summary: This study aims to investigate the impact of CYP3A5 and CYP3A4 genetic variants on fentanyl pharmacokinetics in children using opportunistically collected samples. The results show that genetic variations in the CYP3A5 gene significantly affect fentanyl clearance, while variations in the CYP3A4 gene do not have a significant impact.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Biotechnology & Applied Microbiology
Daniel L. Hertz, Julie A. Douglas, Kelley M. Kidwell, Christina L. Gersch, Zeruesenay Desta, Ana-Maria Storniolo, Vered Stearns, Todd C. Skaar, Daniel F. Hayes, N. Lynn Henry, James M. Rae
Summary: This study aimed to identify genetic polymorphisms associated with steady-state letrozole concentrations, revealing that germline variants, including those in the CYP2A6 gene, can influence letrozole concentrations.
PHARMACOGENETICS AND GENOMICS
(2021)
Review
Endocrinology & Metabolism
Ai-Min Yang, Na Cui, Yi-Fei Sun, Gui-Min Hao
Summary: Letrozole, as an aromatase inhibitor, has been widely used in infertility treatments, with its efficacy and safety confirmed by accumulating clinical and basic evidence. This review focuses on the current knowledge of the applications and mechanisms of letrozole in female infertility, and raises various questions on how it could be used more effectively.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Pharmacology & Pharmacy
Stephania Contreras-Castillo, Anita Plaza, Jana Stojanova, Gustavo Navarro, Rodolfo Carmona, Fernando Corvalan, Leslie Cerpa, Christopher Sandoval, Daniel Munoz, Marina Leiva, Luis E. Castaneda, Nayaret Farias, Carolina Alvarez, Gabriel Llull, Sergio Mezzano, Leopoldo Ardiles, Nelson Varela, Maria S. Rodriguez, Claudio Flores, Juan Pablo Cayun, Paola Krall, Luis A. Quinones
Summary: The study found that CYP3A5*3/*3 carriers required lower doses of TAC in Chilean kidney transplant recipients, with these carriers having higher C-0/D and a higher proportion of patients with trough concentrations outside the therapeutic range.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Infectious Diseases
Taimour Langaee, Mohammad H. Al-Shaer, Yan Gong, Elizabeth Lima, Sampson Antwi, Anthony Enimil, Albert Dompreh, Hongmei Yang, Wael A. Alghamdi, Lubbe Wiesner, Charles A. Peloquin, Awewura Kwara
Summary: In Ghanaian children living with HIV eligible for NVP-based antiretroviral therapy, genetic variations in genes such as CYP2B6 rs3745274 and NR1I2 rs6785049 may serve as predictors of NVP pharmacokinetic parameters, aiding in individualized therapy.
INFECTION GENETICS AND EVOLUTION
(2021)
Article
Multidisciplinary Sciences
Natnicha Wankaew, Pajaree Chariyavilaskul, Monpat Chamnanphon, Adjima Assawapitaksakul, Wanna Chetruengchai, Monnat Pongpanich, Vorasuk Shotelersuk
Summary: Differences in drug responses among individuals can be attributed to genetic variations in pharmacogenes, which vary among populations. In this study, genome sequencing of Thai individuals revealed multiple pharmacogenes with variant phenotypes, including several high impact variants not previously reported. These findings provide valuable information for implementing pharmacogenetic testing in Thailand and other Southeast Asian countries, bringing personalized medicine a step closer.
Review
Pharmacology & Pharmacy
Hiroshi Yamazaki, Makiko Shimizu
Summary: Drug oxygenations are mainly mediated by polymorphic cytochromes P450 and flavin-containing monooxygenases, but there are species differences. The study of the roles of human P450 and FMO enzymes in drug oxidation and clinical therapy is important and still requires further development.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Yasuhiro Uno, Shiori Jikuya, Yutaro Noda, Norie Murayama, Hiroshi Yamazaki
Summary: Novel dog cytochromes P450 3A98 (CYP3A98) and CYP3A99 were identified and characterized to be functional and highly identical to human CYP3A4. CYP3A98 was abundantly expressed in the small intestine in combination with liver-specific CYP3A12, while CYP3A99 showed minimal expression and metabolic activity. Dog CYP3A12 and CYP3A98 likely play major roles in drug metabolism in the liver and small intestine, respectively.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Hidetoshi Shimizu, Yukiko Nishimura, Youichi Shiide, Masaki Ueda, Shoko Yokota, Yuichiro Kato, Manabu Hirai
Summary: This study compared the relative bioavailability of edaravone oral suspension and nasogastric tube administration. The results showed similar plasma concentration-time profiles of unchanged edaravone between the two administration routes. Oral administration did not require dose adjustment and both oral and nasogastric tube administration were well tolerated.
CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT
(2023)
Article
Pharmacology & Pharmacy
Genki Ushirozako, Yutaro Noda, Norie Murayama, Hiroaki Kawaguchi, Kyoko Tsukiyama-Kohara, Hiroshi Yamazaki, Yasuhiro Uno
Summary: The tree shrew, a non-rodent primate-like species, has been widely used in biomedical research for various diseases. Recent genome analysis revealed its similarity to humans in terms of cytochrome P450 (P450 or CYP) genes. However, the comprehensive investigation of P450s in tree shrews is still lacking. In this study, the characteristics of tree shrew CYP2A13 were compared with those of pig, dog, and human CYP2As. It was found that tree shrew CYP2A13 is highly similar to human CYP2As and is expressed in liver and lung.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Shotaro Uehara, Yuichiro Higuchi, Nao Yoneda, Hiroaki Kato, Hiroshi Yamazaki, Hiroshi Suemizu
Summary: Human-specific olanzapine N10-glucuronide isomers were produced in humanized-liver mice, and high UGT1A4-dependent N10-glucuronidation was observed in their liver microsomes. Therefore, humanized-liver mice may be a suitable model for studying UGT1A4-dependent biotransformation of drugs in humans.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Makiko Shimizu, Akane Yamamoto, Miaki Makiguchi, Erika Shimamura, Yuka Yokota, Mizuki Harano, Hiroshi Yamazaki
Summary: Phenotype-gene analyses and mega-databases have identified impaired FMO3 variants associated with trimethylaminuria. This study found a novel compound variant of FMO3 in a 1-year-old Japanese girl and another novel compound variant in a 7-year-old girl. Family studies revealed similar FMO3 metabolic capacities in individuals with the same variants. These variants could impact drug clearance.
DRUG METABOLISM AND PHARMACOKINETICS
(2023)
Article
Pharmacology & Pharmacy
Koichiro Adachi, Katsuhiro Ohyama, Yoichi Tanaka, Tasuku Sato, Norie Murayama, Makiko Shimizu, Yoshiro Saito, Hiroshi Yamazaki
Summary: Drug interactions between atorvastatin and cytochrome P450 (P450) 3A substrates/inhibitors can cause increased skeletal muscle or hepatic toxicity. A survey of 483 Japanese subjects found that over half of them experienced statin intolerance when taking atorvastatin alone. Impaired allele CYP3A4*16 may be a contributing causal factor for statin intolerance, leading to higher plasma and hepatic exposures of atorvastatin.
DRUG METABOLISM AND PHARMACOKINETICS
(2023)
Article
Biochemistry & Molecular Biology
Shotaro Uehara, Yuichiro Higuchi, Nao Yoneda, Ryoji Ito, Takeshi Takahashi, Norie Murayama, Hiroshi Yamazaki, Kazuhiro Murai, Hayato Hikita, Tetsuo Takehara, Hiroshi Suemizu
Summary: Experimental human hepatocytes (HepaSH cells) with less inter-individual differences in drug-metabolizing properties can be stably and reproducibly produced in mice, which may substitute for primary human hepatocytes (PHHs) as practical standardized human hepatocytes in drug discovery research.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Miaki Makiguchi, Makiko Shimizu, Yuka Yokota, Erika Shimamura, Eiji Hishinuma, Sakae Saito, Masahiro Hiratsuka, Hiroshi Yamazaki
Summary: This study investigated the single-nucleotide substitutions of FMO3 in the Japanese population, resulting in the identification of various mutations and amino acid substitutions. Functional analysis revealed that many of these FMO3 variants had impaired enzymatic activity, particularly in the N-oxygenation of trimethylamine. Furthermore, mutations located within the conserved binding sites of FMO3 were found to be associated with severely decreased catalytic activity. These findings highlight the importance of understanding FMO3 variants in relation to trimethylaminuria.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Yasuhiro Uno, Saho Morikuni, Mitsuya Shiraishi, Atsushi Asano, Norie Murayama, Hiroshi Yamazaki
Summary: Dog CYP2C94, along with CYP2C21 and CYP2C41, is an important drug-metabolizing enzyme. It is abundantly expressed in the liver and can efficiently catalyze the oxidation of diclofenac, warfarin, and/or omeprazole. Its high sequence identity with human CYP2Cs suggests its potential role in drug clearances in dogs.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Shotaro Uehara, Makiko Shimizu, Hiroshi Suemizu, Hiroshi Yamazaki
Summary: The urinary metabolic ratio of 60-hydroxydexamethasone to dexamethasone is a noninvasive marker for human cytochrome P450 (P450) 3A4/5. In this study, the pharmacokinetics of dexamethasone in humanized-liver mice were investigated after intravenous administration of azamulin, a P450 3A4/5 inhibitor. Significant differences were observed in the plasma and urinary concentrations of 60-hydroxydexamethasone between untreated and azamulin-treated mice, indicating the role of P450 3A4/5 in dexamethasone metabolism. This study suggests that humanized-liver mice treated with azamulin can serve as an in vivo model for metabolically inactivated P450 3A4/5.
DRUG METABOLISM AND PHARMACOKINETICS
(2023)
Article
Chemistry, Medicinal
Haruna Nagayoshi, Norie Murayama, Vitchan Kim, Donghak Kim, Shigeo Takenaka, Hiroshi Yamazaki, F. Peter Guengerich, Tsutomu Shimada
Summary: This study revealed the oxidation reactions of naringenin and related compounds by human P450 enzymes and compared them with plant enzymes. The results showed that human CYP1 enzymes and CYP2A13 play important roles in the oxidation of naringenin, eriodictyol, apigenin, and genistein, and that human CYP1B1 shares similarities with Scutellaria CYP82D.1 in catalyzing the 6-hydroxylation reactions of apigenin and chrysin.
CHEMICAL RESEARCH IN TOXICOLOGY
(2023)
Article
Oncology
Yutaro Koide, Naoya Nagai, Risei Miyauchi, Tomoki Kitagawa, Takahiro Aoyama, Hidetoshi Shimizu, Shingo Hashimoto, Hiroyuki Tachibana, Takeshi Kodaira
Summary: This study investigated 800 newly diagnosed patients with brain metastases between 2016 and 2021 to evaluate patient characteristics, recent treatment changes, and the percentage of candidates in clinical trials. The study aimed to evaluate recent trends in characteristics and treatments among patients with brain metastases in clinical practice. The results revealed the changing trends in brain metastases treatment modalities and the proportion of candidates in clinical trials.
JAPANESE JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Pharmacology & Pharmacy
Yasuhiro Uno, Saho Morikuni, Norie Murayama, Hiroshi Yamazaki
Summary: The 2-oxidation, 3-methyl hydroxylation, and 6-hydroxylation reactions of skatole were studied using minipig liver microsomes and recombinant P450 enzymes. The formation rates of certain metabolites in male minipig liver microsomes were lower than those in female minipig liver microsomes, and compensatory reactions were observed. Among the different P450 forms evaluated, P450 2A19 was the dominant form mediating the formation of certain metabolites.
Article
Pharmacology & Pharmacy
Makiko Shimizu, Miaki Makiguchi, Yuka Yokota, Erika Shimamura, Moegi Matsuta, Yuria Nakamura, Mizuki Harano, Hiroshi Yamazaki
Summary: Forty-seven new nonsense or missense variants of human FMO3 were identified in a Japanese population. Among these variants, 20 resulted in impaired FMO3 activity. Simple confirmation methods using PCR-RFLP or allele-specific PCR were proposed to easily identify these variants in a clinical setting. These systems facilitate the detection of FMO3 variants in Japanese subjects susceptible to low drug clearance caused by impaired FMO3 function.
DRUG METABOLISM AND PHARMACOKINETICS
(2023)