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Article ; Online: Impact of loperamide on the pharmacokinetics and tissue disposition of ritonavir-boosted oral docetaxel therapy; a preclinical assessment.

Loos, Nancy H C / Bui, Viët / de Jong, Daniëlle H / Lebre, Maria C / Rosing, Hilde / Beijnen, Jos H / Schinkel, Alfred H

Cancer chemotherapy and pharmacology

2024

Abstract: ... loperamide and two of its active metabolites were measured.: Results: The plasma exposure (AUC and C ...

Abstract	Purpose: An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3 A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel. Methods: We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured. Results: The plasma exposure (AUC and C Conclusion: These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.
Language	English
Publishing date	2024-03-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-024-04662-8
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Article ; Online: The ABCB1 and ABCG2 efflux transporters limit brain disposition of the SYK inhibitors entospletinib and lanraplenib.

Loos, Nancy H C / Sparidans, Rolf W / Heydari, Paniz / Bui, Viët / Lebre, Maria C / Beijnen, Jos H / Schinkel, Alfred H

Toxicology and applied pharmacology

2024 Volume 485, Page(s) 116911

Abstract: The highly selective Spleen Tyrosine Kinase (SYK) inhibitors entospletinib and lanraplenib disrupt kinase activity and inhibit immune cell functions. They are developed for treatment of B-cell malignancies and autoimmunity diseases. The impact of P-gp/ ... ...

Abstract	The highly selective Spleen Tyrosine Kinase (SYK) inhibitors entospletinib and lanraplenib disrupt kinase activity and inhibit immune cell functions. They are developed for treatment of B-cell malignancies and autoimmunity diseases. The impact of P-gp/ABCB1 and BCRP/ABCG2 efflux transporters, OATP1a/1b uptake transporters and CYP3A drug-metabolizing enzymes on the oral pharmacokinetics of these drugs was assessed using mouse models. Entospletinib and lanraplenib were orally administered simultaneously at moderate dosages (10 mg/kg each) to female mice to assess the possibility of examining two structurally and mechanistically similar drugs at the same time, while reducing the number of experimental animals and sample-processing workload. The plasma pharmacokinetics of both drugs were not substantially restricted by Abcb1 or Abcg2. The brain-to-plasma ratios of entospletinib in Abcb1a/b
MeSH term(s)	Animals ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; Female ; Mice ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/pharmacology ; Brain/metabolism ; Brain/drug effects ; Syk Kinase/antagonists & inhibitors ; Syk Kinase/metabolism ; Mice, Knockout ; ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors ; Mice, Inbred C57BL ; Pyrimidines/pharmacokinetics ; Pyrimidines/pharmacology ; Administration, Oral ; Indazoles ; Morpholines ; Pyrazines
Chemical Substances	ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Protein Kinase Inhibitors ; Syk Kinase (EC 2.7.10.2) ; 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine ; Abcg2 protein, mouse ; ATP Binding Cassette Transporter, Subfamily B ; Pyrimidines ; Indazoles ; Morpholines ; Pyrazines
Language	English
Publishing date	2024-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2024.116911
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Article ; Online: Microdiverse bacterial clades prevail across Antarctic wetlands.

Quiroga, María V / Stegen, James C / Mataloni, Gabriela / Cowan, Don / Lebre, Pedro H / Valverde, Angel

Molecular ecology

2023 Volume 33, Issue 1, Page(s) e17189

Abstract: Antarctica's extreme environmental conditions impose selection pressures on microbial communities. Indeed, a previous study revealed that bacterial assemblages at the Cierva Point Wetland Complex (CPWC) are shaped by strong homogeneous selection. Yet ... ...

Abstract	Antarctica's extreme environmental conditions impose selection pressures on microbial communities. Indeed, a previous study revealed that bacterial assemblages at the Cierva Point Wetland Complex (CPWC) are shaped by strong homogeneous selection. Yet which bacterial phylogenetic clades are shaped by selection processes and their ecological strategies to thrive in such extreme conditions remain unknown. Here, we applied the phyloscore and feature-level βNTI indexes coupled with phylofactorization to successfully detect bacterial monophyletic clades subjected to homogeneous (HoS) and heterogenous (HeS) selection. Remarkably, only the HoS clades showed high relative abundance across all samples and signs of putative microdiversity. The majority of the amplicon sequence variants (ASVs) within each HoS clade clustered into a unique 97% sequence similarity operational taxonomic unit (OTU) and inhabited a specific environment (lotic, lentic or terrestrial). Our findings suggest the existence of microdiversification leading to sub-taxa niche differentiation, with putative distinct ecotypes (consisting of groups of ASVs) adapted to a specific environment. We hypothesize that HoS clades thriving in the CPWC have phylogenetically conserved traits that accelerate their rate of evolution, enabling them to adapt to strong spatio-temporally variable selection pressures. Variable selection appears to operate within clades to cause very rapid microdiversification without losing key traits that lead to high abundance. Variable and homogeneous selection, therefore, operate simultaneously but on different aspects of organismal ecology. The result is an overall signal of homogeneous selection due to rapid within-clade microdiversification caused by variable selection. It is unknown whether other systems experience this dynamic, and we encourage future work evaluating the transferability of our results.
MeSH term(s)	Phylogeny ; Antarctic Regions ; Wetlands ; Bacteria/genetics ; Microbiota
Language	English
Publishing date	2023-11-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.17189
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Article ; Online: Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice.

Loos, Nancy H C / Martins, Margarida L F / de Jong, Daniëlle / Lebre, Maria C / Tibben, Matthijs / Beijnen, Jos H / Schinkel, Alfred H

Molecular pharmaceutics

2023 Volume 20, Issue 5, Page(s) 2477–2489

Abstract: There is currently great interest in developing oral taxanes due to their lower costs and greater patient friendliness. We here wanted to test whether oral ritonavir, a cytochrome P450 3A (CYP3A) inhibitor, could boost the pharmacokinetics and tissue ... ...

Abstract	There is currently great interest in developing oral taxanes due to their lower costs and greater patient friendliness. We here wanted to test whether oral ritonavir, a cytochrome P450 3A (CYP3A) inhibitor, could boost the pharmacokinetics and tissue distribution of orally administered cabazitaxel (10 mg/kg) in male wild-type,
MeSH term(s)	Male ; Humans ; Mice ; Animals ; Ritonavir ; Cytochrome P-450 CYP3A/metabolism ; Drug Interactions ; Taxoids ; Enzyme Inhibitors/pharmacology ; Biological Availability ; Cytochrome P-450 CYP3A Inhibitors
Chemical Substances	Ritonavir (O3J8G9O825) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; cabazitaxel (51F690397J) ; Taxoids ; Enzyme Inhibitors ; Cytochrome P-450 CYP3A Inhibitors
Language	English
Publishing date	2023-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.2c01076
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Zs.A 6250: Show issues

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Article ; Online: Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice.

Loos, Nancy H C / Martins, Margarida L F / de Jong, Daniëlle / Lebre, Maria C / Tibben, Matthijs / Beijnen, Jos H / Schinkel, Alfred H

International journal of pharmaceutics

2023 Volume 650, Page(s) 123708

Abstract: Developing an oral formulation for the chemotherapeutic cabazitaxel might improve its patient-friendliness, costs, and potentially exposure profile. Cabazitaxel oral availability is restricted by CYP3A-mediated first-pass metabolism, but can be ... ...

Abstract	Developing an oral formulation for the chemotherapeutic cabazitaxel might improve its patient-friendliness, costs, and potentially exposure profile. Cabazitaxel oral availability is restricted by CYP3A-mediated first-pass metabolism, but can be substantially boosted with the CYP3A inhibitor ritonavir. We here tested whether adding the ABCB1/P-glycoprotein inhibitor elacridar to ritonavir-boosted oral cabazitaxel could further improve its tissue exposure using wild-type, CYP3A4-humanized and Abcb1a/b
MeSH term(s)	Humans ; Mice ; Animals ; Ritonavir ; Cytochrome P-450 CYP3A/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Tissue Distribution ; ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; Brain/metabolism ; Mice, Knockout
Chemical Substances	Ritonavir (O3J8G9O825) ; cabazitaxel (51F690397J) ; Elacridar (N488540F94) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP Binding Cassette Transporter, Subfamily B ; ABCB1 protein, human
Language	English
Publishing date	2023-12-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2023.123708
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Zs.A 1409: Show issues

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Article ; Online: Interplay of Ritonavir-Boosted Oral Cabazitaxel with the Organic Anion-Transporting Polypeptide (OATP) Uptake Transporters and Carboxylesterase 1 in Mice.

Loos, Nancy H C / Ferreira Martins, Margarida L / Rijmers, Jamie / de Jong, Daniëlle / Lebre, Maria C / Tibben, Matthijs / Beijnen, Jos H / Schinkel, Alfred H

Molecular pharmaceutics

2024 Volume 21, Issue 4, Page(s) 1952–1964

Abstract: Intravenously administered chemotherapeutic cabazitaxel is used for palliative treatment of prostate cancer. An oral formulation would be more patient-friendly and reduce the need for hospitalization. We therefore study determinants of the oral ... ...

Abstract	Intravenously administered chemotherapeutic cabazitaxel is used for palliative treatment of prostate cancer. An oral formulation would be more patient-friendly and reduce the need for hospitalization. We therefore study determinants of the oral pharmacokinetics of cabazitaxel in a ritonavir-boosted setting, which reduces the CYP3A-mediated first-pass metabolism of cabazitaxel. We here assessed the role of organic anion-transporting polypeptides (OATPs) in the disposition of orally boosted cabazitaxel and its active metabolites, using the Oatp1a/b-knockout and the OATP1B1/1B3-transgenic mice. These transporters may substantially affect plasma clearance and hepatic and intestinal drug disposition. The pharmacokinetics of cabazitaxel and DM2 were not significantly affected by Oatp1a/b and OATP1B1/1B3 activity. In contrast, the plasma AUC
MeSH term(s)	Animals ; Humans ; Male ; Mice ; Carboxylesterase/metabolism ; Docetaxel ; Liver/metabolism ; Liver-Specific Organic Anion Transporter 1/metabolism ; Mice, Transgenic ; Organic Anion Transporters/metabolism ; Organic Anion Transporters, Sodium-Independent/metabolism ; Ritonavir ; Solute Carrier Organic Anion Transporter Family Member 1B3/metabolism ; Taxoids
Chemical Substances	cabazitaxel (51F690397J) ; Carboxylesterase (EC 3.1.1.1) ; Docetaxel (15H5577CQD) ; Liver-Specific Organic Anion Transporter 1 ; Organic Anion Transporters ; Organic Anion Transporters, Sodium-Independent ; Ritonavir (O3J8G9O825) ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Taxoids
Language	English
Publishing date	2024-02-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.3c01205
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Article: ABCB1 and ABCG2 Control Brain Accumulation and Intestinal Disposition of the Novel ROS1/TRK/ALK Inhibitor Repotrectinib, While OATP1A/1B, ABCG2, and CYP3A Limit Its Oral Availability.

Li, Wenlong / Sparidans, Rolf W / Lebre, Maria C / Beijnen, Jos H / Schinkel, Alfred H

Pharmaceutics

2021 Volume 13, Issue 11

Abstract: Repotrectinib shows high activity against ROS1/TRK/ALK fusion-positive cancers in preclinical studies. We explored the roles of multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporter(s), and the CYP3A complex in pharmacokinetics ... ...

Abstract	Repotrectinib shows high activity against ROS1/TRK/ALK fusion-positive cancers in preclinical studies. We explored the roles of multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporter(s), and the CYP3A complex in pharmacokinetics and tissue distribution of repotrectinib in genetically modified mouse models. In vitro, human ABCB1 and ABCG2, and mouse Abcg2 efficiently transported repotrectinib with efflux transport ratios of 13.5, 5.6, and 40, respectively. Oral repotrectinib (10 mg/kg) showed higher plasma exposures in Abcg2-deficient mouse strains. Brain-to-plasma ratios were increased in
Language	English
Publishing date	2021-10-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics13111761
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Article ; Online: ABCB1 and ABCG2, but not CYP3A4 limit oral availability and brain accumulation of the RET inhibitor pralsetinib.

Wang, Yaogeng / Sparidans, Rolf W / Potters, Sander / Lebre, Maria C / Beijnen, Jos H / Schinkel, Alfred H

Pharmacological research

2021 Volume 172, Page(s) 105850

Abstract: Background and purpose: Pralsetinib is an FDA-approved oral small-molecule inhibitor for treatment of rearranged during transfection (RET) proto-oncogene fusion-positive non-small cell lung cancer. We investigated how the efflux transporters ABCB1 and ... ...

Abstract	Background and purpose: Pralsetinib is an FDA-approved oral small-molecule inhibitor for treatment of rearranged during transfection (RET) proto-oncogene fusion-positive non-small cell lung cancer. We investigated how the efflux transporters ABCB1 and ABCG2, the SLCO1A/1B uptake transporters and the drug-metabolizing enzyme CYP3A influence pralsetinib pharmacokinetics. Experimental approach: In vitro, transepithelial pralsetinib transport was assessed. In vivo, pralsetinib (10 mg/kg) was administered orally to relevant genetically modified mouse models. Pralsetinib concentrations in cell medium, plasma samples and organ homogenates were measured using liquid chromatography-tandem mass spectrometry. Key results: Pralsetinib was efficiently transported by human (h)ABCB1 and mouse (m)Abcg2, but not hACBG2. In vivo, mAbcb1a/1b markedly and mAbcg2 slightly limited pralsetinib brain penetration (6.3-and 1.8-fold, respectively). Testis distribution showed similar results. Abcb1a/1b;Abcg2 Conclusions and implications: SLCO1A/1B and CYP3A4 are unlikely to affect the pharmacokinetics of pralsetinib, but ABCG2 and especially ABCB1 markedly limit its brain and testis penetration, as well as oral availability. These effects are mostly reversed by oral coadministration of the ABCB1/ABCG2 inhibitor elacridar. These insights may be useful in the further clinical development of pralsetinib.
MeSH term(s)	Administration, Oral ; Animals ; Antineoplastic Agents/blood ; Antineoplastic Agents/pharmacokinetics ; Biological Availability ; Brain/metabolism ; Cytochrome P-450 CYP3A/genetics ; Female ; Male ; Mice, Knockout ; Organic Anion Transporters/antagonists & inhibitors ; Organic Anion Transporters/genetics ; Organic Anion Transporters/metabolism ; Protein Kinase Inhibitors/blood ; Protein Kinase Inhibitors/pharmacokinetics ; Proto-Oncogene Proteins c-ret/antagonists & inhibitors ; Pyrazoles/blood ; Pyrazoles/pharmacokinetics ; Pyridines/blood ; Pyridines/pharmacokinetics ; Pyrimidines/blood ; Pyrimidines/pharmacokinetics ; Testis/metabolism ; Mice
Chemical Substances	Antineoplastic Agents ; Organic Anion Transporters ; Protein Kinase Inhibitors ; Pyrazoles ; Pyridines ; Pyrimidines ; pralsetinib ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Proto-Oncogene Proteins c-ret (EC 2.7.10.1)
Language	English
Publishing date	2021-08-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2021.105850
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Zs.A 721: Show issues

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Article: P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure.

Wang, Jing / Susam, M Merve / Gan, Changpei / Sparidans, Rolf W / Lebre, Maria C / Beijnen, Jos H / Schinkel, Alfred H

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 9

Abstract: EAI045 is a fourth-generation allosteric tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR). It targets T790M and C797S EGFR mutants in the treatment of non-small cell lung cancer (NSCLC). EAI045 and cetuximab combined induce ... ...

Abstract	EAI045 is a fourth-generation allosteric tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR). It targets T790M and C797S EGFR mutants in the treatment of non-small cell lung cancer (NSCLC). EAI045 and cetuximab combined induce tumor regression in mouse models of EGFR-mutant lung cancer. We investigated the pharmacokinetic roles of the multidrug efflux and uptake transporters ABCB1 (P-gp), ABCG2 (BCRP), and OATP1A/1B, and of the drug-metabolizing enzyme CYP3A in plasma and tissue distribution of EAI045 and its metabolites, using genetically modified mouse models. In vitro, EAI045 was a good transport substrate of human ABCB1. In vivo, oral EAI045 (20 mg/kg) was rapidly absorbed. Relative to wild-type mice, EAI045 brain-to-plasma ratios were increased 3.9-fold in
Language	English
Publishing date	2022-09-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15091124
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Article ; Online: ABCB1 restricts brain accumulation of the novel RORγ agonist cintirorgon, while OATP1A/1B and CYP3A limit its oral availability.

Li, Wenlong / Lehutová, Daniela / Sparidans, Rolf W / Heydari, Paniz / Wang, Jing / Lebre, Maria C / Beijnen, Jos H / Schinkel, Alfred H

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

2022 Volume 177, Page(s) 135–146

Abstract: Cintirorgon (LYC-55716), a first-in-class, small-molecule, oral selective RORγ agonist, has been developed as a new immuno-oncology drug for solid tumors. We here studied the functions of the ABCB1 and ABCG2 multidrug efflux transporters, the OATP1A/1B ... ...

Abstract	Cintirorgon (LYC-55716), a first-in-class, small-molecule, oral selective RORγ agonist, has been developed as a new immuno-oncology drug for solid tumors. We here studied the functions of the ABCB1 and ABCG2 multidrug efflux transporters, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A enzyme complex in cintirorgon pharmacokinetics using genetically modified mouse models. Cintirorgon was modestly transported by human ABCB1 and mouse Abcg2 in vitro. Upon oral administration at 40 mg/kg, net cintirorgon brain penetration was enhanced in Abcb1a/1b
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Animals ; Benzoxazines ; Brain/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Dogs ; Humans ; Madin Darby Canine Kidney Cells ; Mice ; Mice, Knockout ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Organic Anion Transporters/metabolism ; Propionates
Chemical Substances	ABCB1 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Benzoxazines ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Organic Anion Transporters ; Propionates ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; cintirorgon (LPN433P0EA)
Language	English
Publishing date	2022-06-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1065368-5
ISSN	1873-3441 ; 0939-6411
ISSN (online)	1873-3441
ISSN	0939-6411
DOI	10.1016/j.ejpb.2022.06.008
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