Article
Medicine, Research & Experimental
Margarida L. F. Martins, Nancy H. C. Loos, Sumeyra Mucuk, Danielle de Jong, Maria C. Lebre, Hilde Rosing, Matthijs Tibben, Jos H. Beijnen, Alfred H. Schinkel
Summary: The study found that Abcb1 deficiency significantly increased the distribution of niraparib in the brain and reduced its recovery in the small intestine, which was completely inhibited by Elacridar pretreatment. OATP1 and CYP3A had minimal impact on the metabolism and distribution of niraparib, which could be advantageous in reducing the risk of drug-drug interactions or interindividual variation.
MOLECULAR PHARMACEUTICS
(2021)
Article
Chemistry, Multidisciplinary
Severin Mairinger, Irene Hern, Thomas Filip, Michael Sauberer, Mathilde Lobsch, Johann Stanek, Thomas Wanek, Johannes A. Sake, Thomas Pekar, Carsten Ehrhardt, Oliver Langer
Summary: This study used positron emission tomography (PET) imaging to investigate the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on the pulmonary distribution of inhaled drugs. The results showed functional activity of P-gp and BCRP in the lungs and suggested that these transporters play a role in limiting the uptake of drugs in the lungs, similar to the blood-brain barrier. The study highlights the importance of pulmonary efflux transporters in the efficacy and safety of inhaled drugs.
JOURNAL OF CONTROLLED RELEASE
(2022)
Article
Chemistry, Medicinal
Reiko Watanabe, Tsuyoshi Esaki, Rikiya Ohashi, Masataka Kuroda, Hitoshi Kawashima, Hiroshi Komura, Yayoi Natsume-Kitatani, Kenji Mizuguchi
Summary: A computer model was developed to predict the efflux potential of drugs through brain capillary endothelial cells' P-gp, proposing a novel system for evaluating brain-to-plasma concentration ratios of P-gp substrates. Validation with experimental data improved the accuracy of predicting drug penetration across the blood-brain barrier, solely based on chemical structure information, compared to previous studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Vinaya Phatak, Yannick von Grabowiecki, Justyna Janus, Leah Officer, Caron Behan, Lydia Aschauer, Lucia Pinon, Hannah Mackay, Sara Zanivan, Jim C. Norman, Michael Kelly, John Le Quesne, Patricia A. J. Muller
Summary: Mutant p53 protein can facilitate the cell membrane recycling of P-gp through RCP, leading to chemoresistance. Cells without RCP or mutant p53 show increased sensitivity to cisplatin and etoposide.
CELL DEATH & DISEASE
(2021)
Article
Pharmacology & Pharmacy
Alejandra Martinez-Chavez, Nancy H. C. Loos, Maria C. Lebre, Matthijs M. Tibben, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel
Summary: The study reveals that both ABCB1 and ABCG2 proteins profoundly limit the brain penetration of abemaciclib and its active metabolites, and are likely involved in their elimination through the liver, bile, or intestines. Additionally, the human CYP3A4 gene significantly reduces the plasma concentration of abemaciclib, highlighting its importance in the clinical development of abemaciclib for brain malignancies.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Pharmacology & Pharmacy
Alejandra Martinez-Chavez, Jelle Broeders, Maria C. Lebre, Matthijs T. Tibben, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel
Summary: The pharmacokinetics of the promising anticancer drug milciclib is influenced by various transporters and drug-metabolizing enzymes, with ABCB1 and ABCG2 cooperatively limiting its brain penetration.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Takafumi Kato, Tsuyoshi Mikkaichi, Yasushi Yoshigae, Noriko Okudaira, Takako Shimizu, Takashi Izumi, Shuichi Ando, Yoshiaki Matsumoto
Summary: The study evaluates the impact of P-gp efflux on edoxaban absorption in gastrointestinal tracts quantitatively using a PBPK model. The constructed model successfully demonstrates the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Pharmacology & Pharmacy
Margarida L. F. Martins, Paniz Heydari, Wenlong Li, Alejandra Martinez-Chavez, Nikkie Venekamp, Maria C. Lebre, Luc Lucas, Jos H. Beijnen, Alfred H. Schinkel
Summary: This study investigated the impact of drug transporters and drug-metabolizing complex on the pharmacokinetics of ibogaine and its metabolites. The results showed that drug efflux and uptake transporters have a modest restricting effect on the systemic exposure and brain penetration of ibogaine, while drug-metabolizing complex had negligible impact on ibogaine pharmacokinetics.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Thermodynamics
Aurelie Bellemans, Nicholas Kincaid, Nicholas Deak, Perrine Pepiot, Fabrizio Bisetti
Summary: A novel methodology called P-DRGEP has been developed and applied for reducing large detailed plasma-assisted combustion mechanisms to smaller skeletal ones, resulting in a computational speed-up of 84% for ignition simulations with guaranteed errors below 10% and 1% on the time required for ignition following the first pulse and the mean electron energy, respectively. The performance of P-DRGEP was found to be greatly superior to traditional reduction approaches, generating a smaller skeletal mechanism with significantly lower errors for ethylene-air ignition simulations.
PROCEEDINGS OF THE COMBUSTION INSTITUTE
(2021)
Article
Biochemistry & Molecular Biology
Ogochukwu Amaeze, Emily S. Marques, Wei Wei, Sarah Lazzaro, Nathaniel Johnson, Manthena V. S. Varma, Angela Slitt
Summary: This study evaluated the potential herb-drug interactions of V. amygdalina, O. gratissimum, M. oleifera, A. indica, and P. nitida extracts. The results suggested that these herbal extracts can modulate CYP enzymes and P-gp activity, potentially causing herb-drug interactions in vivo.
CURRENT DRUG METABOLISM
(2021)
Article
Chemistry, Multidisciplinary
Gul Cetin, Bunyamin Tras, Kamil Uney
Summary: This study investigated the effects of FEX and DEX with P-gp modulators on the distribution of LVX in rat brain, testicle, and plasma. The results showed that the dose and time of DEX administration could affect the passage of LVX to the brain and testicle tissue.
Article
Pharmacology & Pharmacy
Yuheng Shan, Yuying Cen, Yanjin Zhang, Ruishu Tan, Jiahua Zhao, Zhiyong Nie, Jiatang Zhang, Shengyuan Yu
Summary: The study found that inhibition of P-gp, Bcrp, Mrp2, and Oat3 increased the penetration of acyclovir across the blood-brain barrier, suggesting that these efflux pumps restrict the distribution of acyclovir in the brain.
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS
(2022)
Article
Pharmacology & Pharmacy
Jinfu Peng, Mayur K. Ladumor, Jashvant D. Unadkat
Summary: This study successfully estimated the in vivo fetal-to-maternal unbound steady-state plasma concentration ratio (K-p,K-uu,K-fetal) of nelfinavir (P-gp substrate), efavirenz (BCRP substrate), and imatinib (P-gp and BCRP substrate) using maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) modeling. These K-p,K-uu,K-fetal values can be used to adjust dosing regimens of these drugs to optimize maternal-fetal drug therapy throughout pregnancy, to assess fetal benefits and risks of these dosing regimens, and to determine if these estimated in vivo K-p,K-uu,K-fetal values can be predicted from in vitro studies.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Chemistry, Medicinal
Yanan Wang, Min Zhang, Xue Zhou, Chengbo Xu, Chenggen Zhu, Yuhe Yuan, Naihong Chen, Yongchun Yang, Qinglan Guo, Jiangong Shi
Summary: A study isolated and characterized various new compounds from tian ma. During extraction and refluxing processes, p-hydroxybenzyl alcohol underwent condensation reactions to produce more effective dimeric and trimeric derivatives. These derivatives showed stronger activities than the original constituents, providing new insights into the application of traditional Chinese medicines.
NATURAL PRODUCTS AND BIOPROSPECTING
(2021)