Article
Plant Sciences
Sara Abdelfatah, Madeleine Boeckers, Maitane Asensio, Onat Kadioglu, Anette Klinger, Edmond Fleischer, Thomas Efferth
Summary: The study identified isopetasin and S-isopetasin as novel P-gp inhibitors, which can overcome multidrug resistance and induce ROS generation and apoptosis in cancer cells.
Article
Chemistry, Medicinal
Yueyue Liu, Qian Zhang, Chao Lu, Wei Hu
Summary: The study evaluated the impact of itraconazole on the safety and pharmacokinetics of pyrotinib in Chinese healthy adults. Co-administration of itraconazole substantially increased the exposure to pyrotinib without causing serious adverse events, indicating good tolerability of the combination therapy in healthy participants.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2021)
Article
Chemistry, Multidisciplinary
Lu Liu, Wei Li, Le Yang, Zi-tao Guo, Hao Xue, Ning-jie Xie, Xiao-yan Chen
Summary: Almonertinib, a novel EGFR tyrosine kinase inhibitor, is metabolized by CYP3A, with the major active metabolite being N-desmethyl almonertinib (HAS-719). Co-administration with itraconazole increased almonertinib levels but reduced HAS-719 levels, while rifampicin decreased levels of both almonertinib and HAS-719. Further metabolism of HAS-719 may contribute to its altered pharmacokinetics when combined with rifampicin.
ACTA PHARMACOLOGICA SINICA
(2022)
Article
Biochemistry & Molecular Biology
Keerthana Sasitharan, Hamzah Asad Iqbal, Foteini Bifsa, Aleksandra Olszewska, Kenneth J. Linton
Summary: The study investigates the role of hydrogen bonds and specific glutamines in drug recognition and transport by the ABCB1 efflux transporter. Results show that different glutamine mutations have varying effects on the transport of different drug classes, suggesting a complex mechanism of drug recognition. Surprisingly, some mutations improved drug transport, highlighting the intricate interactions within the drug binding pocket of ABCB1.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Yasmeen Cheema, Yusra Sajid Kiani, Kenneth J. J. Linton, Ishrat Jabeen
Summary: Researchers developed a pharmacophore model based on the cryo-EM structure of ABCB1 to screen for new inhibitors, resulting in the identification of six potential inhibitors with distinct chemistries and favorable properties. The compounds exhibited low nanomolar range inhibitory concentrations and two of them were able to resensitize ABCB1-expressing cells to taxol. This study demonstrates the utility of cryo-electron microscopy in drug identification and design.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Gangyang Wang, Lingling Cao, Yafei Jiang, Tao Zhang, Hongsheng Wang, Zhuoying Wang, Jing Xu, Min Mao, Yingqi Hua, Zhengdong Cai, Xiaojun Ma, Shuo Hu, Chenghao Zhou
Summary: This study demonstrates that anlotinib can reverse multidrug resistance in osteosarcoma cells by inhibiting the efflux function of P-glycoprotein 1 (PGP1) and increasing the intracellular accumulation of chemotherapeutic agents. Anlotinib also stimulates the ATPase activity of PGP1. In animal studies, anlotinib combined with doxorubicin shows a significant decrease in tumor growth rate and tumor size.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Laura Braconi, Silvia Dei, Marialessandra Contino, Chiara Riganti, Gianluca Bartolucci, Dina Manetti, Maria Novella Romanelli, Maria Grazia Perrone, Nicola Antonio Colabufo, Stefano Guglielmo, Elisabetta Teodori
Summary: New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized and studied as MDR reversers, showing potent inhibitory effects on P-gp transport activity and increasing the antiproliferative effect of doxorubicin in MDR cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Liadys Mora Lagares, Yunierkis Perez-Castillo, Nikola Minovski, Marjana Novic
Summary: P-gp is an important protein involved in drug efflux and multidrug resistance. Molecular dynamics simulations can provide valuable insights into the binding behavior and conformational changes of P-gp in the presence of different compounds.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Louise Breuil, Nora Ziani, Sarah Leterrier, Gaelle Hugon, Fabien Caille, Viviane Bouilleret, Charles Truillet, Maud Goislard, Myriam El Biali, Martin Bauer, Oliver Langer, Sebastien Goutal, Nicolas Tournier
Summary: This study investigated the impact of CYP inducers and inhibitors on the brain and plasma kinetics of [C-11]metoclopramide using PET imaging. The results showed that CYP induction or inhibition had negligible effects on the plasma kinetics and metabolism of [C-11]metoclopramide, but ritonavir significantly increased brain penetration.
Article
Pharmacology & Pharmacy
Keli Wang, Juefang Ding, Xianjing Li, Wenjing Guo, Xingyu Zhu, Yue Su, Luning Sun, Huan Zhou, Li Ding
Summary: This study investigated the drug-drug interactions of Youkenafil. The results showed that Youkenafil was mainly metabolized through CYP3A4/5. Itraconazole increased the concentration of Youkenafil and its metabolite M1, while rifampicin reduced the concentration of Youkenafil. Therefore, co-administration of Youkenafil with potent inhibitors or inducers of CYP3A4/5 should be avoided or carefully monitored.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Sho Shimazaki, Junko Kuroda, Kenju Shimomura, Shingen Misaka
Summary: The study suggests that measuring the urinary excretion of nadolol can be a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P-glycoprotein-mediated drug interactions.
JOURNAL OF CLINICAL PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Louise Breuil, Sebastien Goutal, Solene Marie, Antonio Del Vecchio, Davide Audisio, Amelie Soyer, Maud Goislard, Wadad Saba, Nicolas Tournier, Fabien Caille
Summary: This study compared the efflux and brain exposure of domperidone and metoclopramide at the blood-brain barrier using PET imaging. The results showed that domperidone had lower penetration and exposure in the brain compared to metoclopramide.
Article
Endocrinology & Metabolism
Louise Breuil, Solene Marie, Sebastien Goutal, Sylvain Auvity, Charles Truillet, Wadad Saba, Oliver Langer, Fabien Caille, Nicolas Tournier
Summary: This study investigates differences in vulnerability to P-gp inhibition among radiolabeled substrates and emphasizes the importance of considering partial inhibition of transporter function as a primary criterion in evaluating the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function in vivo.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2021)
Article
Oncology
Kunhong Deng, Yi Zou, Chan Zou, Hong Wang, Yuxia Xiang, Xiaoyan Yang, Shuang Yang, Chang Cui, Guoping Yang, Jie Huang
Summary: This study aimed to investigate the pharmacokinetic characteristics and safety of the combination of the strong CYP3A4-metabolizing enzyme inhibitor itraconazole and the novel oral Enhancer of Zeste Homolog 2 inhibitor SHR2554. The results showed that the combination of itraconazole and SHR2554 significantly increased the plasma concentration of SHR2554. The combination regimen was well tolerated and had a good safety profile.
Article
Biochemistry & Molecular Biology
Catia A. Bonito, Ricardo J. Ferreira, Maria-Jose U. Ferreira, Jean-Pierre Gillet, M. Natalia D. S. Cordeiro, Daniel J. V. A. dos Santos
Summary: In this study, the impact of four P-gp mutations on drug-binding and efflux-related signal-transmission mechanism was evaluated. The repacking of the transmembrane helices induced by mutations and ligands indicates P-gp's sensitivity to perturbations in the transmembrane region. Changes in drug-binding were observed as a consequence of transmembrane helices repacking, but were not always correlated with alterations in ligand binding mode and affinity. The changes in drug efflux are mostly related to changes in drug specificity rather than effects on signal-transmission mechanism.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Review
Pharmacology & Pharmacy
Laura B. Ramsey, Li Gong, Seung-Been Lee, Jonathan B. Wagner, Xujia Zhou, Katrin Sangkuhl, Solomon M. Adams, Robert J. Straka, Philip E. Empey, Erin C. Boone, Teri E. Klein, Mikko Niemi, Andrea Gaedigk
Summary: PharmVar provides star allele nomenclature for the SLCO1B1 gene, which plays an important role in drug transport and metabolism. The standardized nomenclature has been adopted by CPIC and incorporated into guidelines.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Marie-Noeurolle Paludetto, Mika Kurkela, Helina Kahma, Janne T. Backman, Mikko Niemi, Anne M. Filppula
Summary: This study aimed to explore the cytochrome P450 metabolic and inhibitory profile of hydroxychloroquine (HCQ). The results showed that CYP3A4, CYP2D6, and CYP2C8 are the key enzymes involved in HCQ metabolism. HCQ and its metabolites showed reversible inhibition of CYP2D6 and time-dependent inhibition of CYP3A. Rating: 8/10.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Pharmacology & Pharmacy
Feng Deng, Maren Laasik, Liina Salminen, Lauri Lapatto, Kaisa Huhtinen, Yilin Li, Sampsa Hautaniemi, Johanna Hynninen, Mikko Niemi, Rainer Lehtonen
Summary: The study identified genetic variations in SLCO1B3, LIG3, GSTP1, ABCB1, and OPRM1 associated with risk of adverse effects, treatment response, and prognosis in patients receiving carboplatin-paclitaxel therapy for ovarian cancer.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Hilkka Liedes, Juha Pajula, Anna-Leena Vuorinen, Francesco De Pretis, Mark van Gils, Kari Harno, Mika Lehto, Mikko Niemi, Jaakko Lahteenmaki
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Minna Lehtisalo, Wilma Kiander, Anne M. M. Filppula, Feng Deng, Heidi Kidron, Mari Korhonen, Johanna Sinkko, Kimmo Koivula, Mikko Niemi
Summary: We report 3 cases of rhabdomyolysis diagnosed in patients 1-6 months after the concurrent use of rosuvastatin and ticagrelor. A review of the literature and the Food and Drug Administration adverse event reporting system revealed more than 40 reports of rhabdomyolysis during concomitant ticagrelor and rosuvastatin, including 3 fatal cases. In vitro studies showed that ticagrelor inhibits the transport of rosuvastatin by breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1, with inhibitory concentrations ranging from 0.36 to 7.5 μM. Our findings suggest that the concomitant use of ticagrelor and rosuvastatin may lead to an increased risk of rosuvastatin-induced rhabdomyolysis due to the inhibition of rosuvastatin transport. Further research is needed to investigate the pharmacokinetic interaction between ticagrelor and rosuvastatin in humans.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Johanna Kujala, Niklas Wester, Terhi J. Lohela, Mika Kurkela, Janne T. Backman, Bjorn Mikladal, Tomi Laurila, Jari Koskinen, Tuomas O. Lilius, Eija A. Kalso
Summary: This study aimed to validate a novel electrochemical point-of-care (POC) assay for rapid paracetamol concentration determinations. The results showed biases in POC compared with venous plasma and capillary blood HPLC-MS/MS at concentrations >30 μM. The novel POC method is considered a promising tool for paracetamol concentration analysis.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Medicine, Research & Experimental
Katja Hakkinen, Wilma Kiander, Heidi Kidron, Markku Lahteenvuo, Lea Urpa, Jonne Lintunen, Kati-Sisko Vellonen, Seppo Auriola, Minna Holm, Kaisla Lahdensuo, Olli Kampman, Erkki Isometsa, Tuula Kieseppa, Jouko Lonnqvist, Jaana Suvisaari, Jarmo Hietala, Jari Tiihonen, Aarno Palotie, Ari V. Ahola-Olli, Mikko Niemi
Summary: Six rare SLCO1B1 single nucleotide variants (SNVs) were identified in Finnish individuals with a psychotic disorder, which may affect the expression and functionality of the OATP1B1 protein. Functional studies showed that one of these SNVs (c.629G>T) resulted in the loss of OATP1B1 function and decreased membrane protein expression.
MOLECULAR PHARMACEUTICS
(2023)
Article
Medicine, Research & Experimental
Christine C. Orozco, Mikko Neuvonen, Yi-An Bi, Matthew A. Cerny, Sumathy Mathialagan, Laurie Tylaska, Brian Rago, Chester Costales, Amanda King-Ahmad, Mikko Niemi, A. David Rodrigues
Summary: This study found that sulfated bile acids (BA-S) can potentially serve as clinical biomarkers for OATP1B1/3. The BA-S substrates were observed in OATP1B1, OATP1B3, and NTCP transfected into human embryonic kidney 293 cells, with minimal uptake in other solute carriers (SLCs). Inhibition of BA-S uptake in human hepatocytes was greater with rifampicin (OATP1B1/3 selective inhibitor) than other inhibitors.
MOLECULAR PHARMACEUTICS
(2023)
Article
Pharmacology & Pharmacy
Mirjam Kauppila, Janne T. Backman, Mikko Niemi, Outi Lapatto-Reiniluoto
Summary: The incidence of fatal adverse drug reactions (ADRs) varies widely in hospitals, and these reactions are often not reported. Evaluating the impact of medical safety processes and understanding ADR trends is challenging. In this study, researchers investigated fatal ADRs in a university hospital and compared the results with previous studies. They found that certain drug classes and diseases were associated with the most common fatal ADRs, and improvements in pharmacovigilance awareness were observed.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Feng Deng, Johanna Sistonen, Mikko Neuvonen, Mikko Niemi
Summary: This study evaluated the potential interactions between PARP inhibitors and statins, and found that PARP inhibitors can inhibit certain transporter proteins, potentially increasing the exposure of statins. However, the clinical significance of these interactions is minimal, although they may increase the risk of adverse effects when combined with other predisposing factors.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Aleksi M. Olkkola, Tuija Tapaninen, Aleksi Tornio, Milka Hauta-aho, Outi Lapatto-Reiniluoto, Mikko Neuvonen, Johanna I. Kiiski, Pertti J. Neuvonen, Mikko Niemi, Janne T. Backman
Summary: This study found that the antifungal drug posaconazole significantly increases the exposure level of ibrutinib. Whether posaconazole is taken in the morning or in the evening, it can increase the plasma drug concentration of ibrutinib. Therefore, during posaconazole treatment, the daily dose of ibrutinib should not exceed 70 mg to avoid potential toxicity.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Minna Lehtisalo, E. Katriina Tarkiainen, Mikko Neuvonen, Mikko Holmberg, Johanna I. Kiiski, Outi Lapatto-Reiniluoto, Anne M. Filppula, Mika Kurkela, Janne T. Backman, Mikko Niemi
Summary: Ticagrelor increases the plasma concentration of rosuvastatin in humans, most likely by inhibiting intestinal BCRP. Therefore, concurrent use of ticagrelor and high doses of rosuvastatin should be avoided.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Medicine, Research & Experimental
Markus Ramste, Markus Ritvos, Sergei Hayrynen, Johanna I. Kiiski, Mikko Niemi, Juha Sinisalo
Summary: The aim of this study was to investigate the influence of CYP2C19 loss-of-function variants and CYP2C19 inhibitors, such as omeprazole or esomeprazole, on the incidence of cardiovascular events in patients using clopidogrel. The study found that carriers of CYP2C19 loss-of-function alleles had a higher frequency of cardiovascular events compared to non-carriers. Additionally, the use of omeprazole or esomeprazole was similar between carriers and non-carriers. These findings suggest that both genetics and concomitant medication should be considered for optimal patient care.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2023)