Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice
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 ritonavi...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Loos, Nancy H.C. [verfasserIn] Martins, Margarida L.F. [verfasserIn] de Jong, Daniëlle [verfasserIn] Lebre, Maria C. [verfasserIn] Tibben, Matthijs [verfasserIn] Beijnen, Jos H. [verfasserIn] Schinkel, Alfred H. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2023 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: International journal of pharmaceutics - New York, NY [u.a.] : Elsevier, 1978, 650 |
|---|---|
| Übergeordnetes Werk: |
volume:650 |
| DOI / URN: |
10.1016/j.ijpharm.2023.123708 |
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| Katalog-ID: |
ELV066421764 |
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| 100 | 1 | |a Loos, Nancy H.C. |e verfasserin |0 (orcid)0000-0002-8507-0280 |4 aut | |
| 245 | 1 | 0 | |a Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice |
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| 520 | |a 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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. | ||
| 650 | 4 | |a Cabazitaxel/Jevtana | |
| 650 | 4 | |a Ritonavir | |
| 650 | 4 | |a Cytochrome P450 3A (CYP3A4) | |
| 650 | 4 | |a Elacridar | |
| 650 | 4 | |a P-glycoprotein (P-gp/ABCB1) | |
| 650 | 4 | |a Pharmacokinetics | |
| 700 | 1 | |a Martins, Margarida L.F. |e verfasserin |4 aut | |
| 700 | 1 | |a de Jong, Daniëlle |e verfasserin |4 aut | |
| 700 | 1 | |a Lebre, Maria C. |e verfasserin |0 (orcid)0000-0002-9234-4227 |4 aut | |
| 700 | 1 | |a Tibben, Matthijs |e verfasserin |4 aut | |
| 700 | 1 | |a Beijnen, Jos H. |e verfasserin |4 aut | |
| 700 | 1 | |a Schinkel, Alfred H. |e verfasserin |0 (orcid)0000-0002-4215-8602 |4 aut | |
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10.1016/j.ijpharm.2023.123708 doi (DE-627)ELV066421764 (ELSEVIER)S0378-5173(23)01130-4 DE-627 ger DE-627 rda eng 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl Loos, Nancy H.C. verfasserin (orcid)0000-0002-8507-0280 aut Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. Cabazitaxel/Jevtana Ritonavir Cytochrome P450 3A (CYP3A4) Elacridar P-glycoprotein (P-gp/ABCB1) Pharmacokinetics Martins, Margarida L.F. verfasserin aut de Jong, Daniëlle verfasserin aut Lebre, Maria C. verfasserin (orcid)0000-0002-9234-4227 aut Tibben, Matthijs verfasserin aut Beijnen, Jos H. verfasserin aut Schinkel, Alfred H. verfasserin (orcid)0000-0002-4215-8602 aut Enthalten in International journal of pharmaceutics New York, NY [u.a.] : Elsevier, 1978 650 Online-Ressource (DE-627)301512817 (DE-600)1484643-3 (DE-576)081952708 1873-3476 nnns volume:650 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.40 Pharmazie Pharmazeutika VZ AR 650 |
| spelling |
10.1016/j.ijpharm.2023.123708 doi (DE-627)ELV066421764 (ELSEVIER)S0378-5173(23)01130-4 DE-627 ger DE-627 rda eng 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl Loos, Nancy H.C. verfasserin (orcid)0000-0002-8507-0280 aut Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. Cabazitaxel/Jevtana Ritonavir Cytochrome P450 3A (CYP3A4) Elacridar P-glycoprotein (P-gp/ABCB1) Pharmacokinetics Martins, Margarida L.F. verfasserin aut de Jong, Daniëlle verfasserin aut Lebre, Maria C. verfasserin (orcid)0000-0002-9234-4227 aut Tibben, Matthijs verfasserin aut Beijnen, Jos H. verfasserin aut Schinkel, Alfred H. verfasserin (orcid)0000-0002-4215-8602 aut Enthalten in International journal of pharmaceutics New York, NY [u.a.] : Elsevier, 1978 650 Online-Ressource (DE-627)301512817 (DE-600)1484643-3 (DE-576)081952708 1873-3476 nnns volume:650 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.40 Pharmazie Pharmazeutika VZ AR 650 |
| allfields_unstemmed |
10.1016/j.ijpharm.2023.123708 doi (DE-627)ELV066421764 (ELSEVIER)S0378-5173(23)01130-4 DE-627 ger DE-627 rda eng 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl Loos, Nancy H.C. verfasserin (orcid)0000-0002-8507-0280 aut Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. Cabazitaxel/Jevtana Ritonavir Cytochrome P450 3A (CYP3A4) Elacridar P-glycoprotein (P-gp/ABCB1) Pharmacokinetics Martins, Margarida L.F. verfasserin aut de Jong, Daniëlle verfasserin aut Lebre, Maria C. verfasserin (orcid)0000-0002-9234-4227 aut Tibben, Matthijs verfasserin aut Beijnen, Jos H. verfasserin aut Schinkel, Alfred H. verfasserin (orcid)0000-0002-4215-8602 aut Enthalten in International journal of pharmaceutics New York, NY [u.a.] : Elsevier, 1978 650 Online-Ressource (DE-627)301512817 (DE-600)1484643-3 (DE-576)081952708 1873-3476 nnns volume:650 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.40 Pharmazie Pharmazeutika VZ AR 650 |
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10.1016/j.ijpharm.2023.123708 doi (DE-627)ELV066421764 (ELSEVIER)S0378-5173(23)01130-4 DE-627 ger DE-627 rda eng 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl Loos, Nancy H.C. verfasserin (orcid)0000-0002-8507-0280 aut Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. Cabazitaxel/Jevtana Ritonavir Cytochrome P450 3A (CYP3A4) Elacridar P-glycoprotein (P-gp/ABCB1) Pharmacokinetics Martins, Margarida L.F. verfasserin aut de Jong, Daniëlle verfasserin aut Lebre, Maria C. verfasserin (orcid)0000-0002-9234-4227 aut Tibben, Matthijs verfasserin aut Beijnen, Jos H. verfasserin aut Schinkel, Alfred H. verfasserin (orcid)0000-0002-4215-8602 aut Enthalten in International journal of pharmaceutics New York, NY [u.a.] : Elsevier, 1978 650 Online-Ressource (DE-627)301512817 (DE-600)1484643-3 (DE-576)081952708 1873-3476 nnns volume:650 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.40 Pharmazie Pharmazeutika VZ AR 650 |
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10.1016/j.ijpharm.2023.123708 doi (DE-627)ELV066421764 (ELSEVIER)S0378-5173(23)01130-4 DE-627 ger DE-627 rda eng 610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl Loos, Nancy H.C. verfasserin (orcid)0000-0002-8507-0280 aut Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. Cabazitaxel/Jevtana Ritonavir Cytochrome P450 3A (CYP3A4) Elacridar P-glycoprotein (P-gp/ABCB1) Pharmacokinetics Martins, Margarida L.F. verfasserin aut de Jong, Daniëlle verfasserin aut Lebre, Maria C. verfasserin (orcid)0000-0002-9234-4227 aut Tibben, Matthijs verfasserin aut Beijnen, Jos H. verfasserin aut Schinkel, Alfred H. verfasserin (orcid)0000-0002-4215-8602 aut Enthalten in International journal of pharmaceutics New York, NY [u.a.] : Elsevier, 1978 650 Online-Ressource (DE-627)301512817 (DE-600)1484643-3 (DE-576)081952708 1873-3476 nnns volume:650 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.40 Pharmazie Pharmazeutika VZ AR 650 |
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Enthalten in International journal of pharmaceutics 650 volume:650 |
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Cabazitaxel/Jevtana Ritonavir Cytochrome P450 3A (CYP3A4) Elacridar P-glycoprotein (P-gp/ABCB1) Pharmacokinetics |
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International journal of pharmaceutics |
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Loos, Nancy H.C. @@aut@@ Martins, Margarida L.F. @@aut@@ de Jong, Daniëlle @@aut@@ Lebre, Maria C. @@aut@@ Tibben, Matthijs @@aut@@ Beijnen, Jos H. @@aut@@ Schinkel, Alfred H. @@aut@@ |
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2023-01-01T00:00:00Z |
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Loos, Nancy H.C. |
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Loos, Nancy H.C. ddc 610 ssgn 15,3 fid PHARM bkl 44.40 misc Cabazitaxel/Jevtana misc Ritonavir misc Cytochrome P450 3A (CYP3A4) misc Elacridar misc P-glycoprotein (P-gp/ABCB1) misc Pharmacokinetics Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice |
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610 VZ 15,3 ssgn PHARM DE-84 fid 44.40 bkl Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice Cabazitaxel/Jevtana Ritonavir Cytochrome P450 3A (CYP3A4) Elacridar P-glycoprotein (P-gp/ABCB1) Pharmacokinetics |
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ddc 610 ssgn 15,3 fid PHARM bkl 44.40 misc Cabazitaxel/Jevtana misc Ritonavir misc Cytochrome P450 3A (CYP3A4) misc Elacridar misc P-glycoprotein (P-gp/ABCB1) misc Pharmacokinetics |
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ddc 610 ssgn 15,3 fid PHARM bkl 44.40 misc Cabazitaxel/Jevtana misc Ritonavir misc Cytochrome P450 3A (CYP3A4) misc Elacridar misc P-glycoprotein (P-gp/ABCB1) misc Pharmacokinetics |
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Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice |
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Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice |
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Loos, Nancy H.C. |
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Loos, Nancy H.C. Martins, Margarida L.F. de Jong, Daniëlle Lebre, Maria C. Tibben, Matthijs Beijnen, Jos H. Schinkel, Alfred H. |
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coadministration of abcb1/p-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice |
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Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice |
| 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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. |
| abstractGer |
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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. |
| abstract_unstemmed |
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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. This approach should be verified in selected patient populations. |
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Coadministration of ABCB1/P-glycoprotein inhibitor elacridar improves tissue distribution of ritonavir-boosted oral cabazitaxel in mice |
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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-/- mice. The plasma AUC0-2h of cabazitaxel was increased 2.3- and 1.9-fold in the ritonavir- and ritonavir-plus-elacridar groups of wild-type, and 10.5- and 8.8-fold in CYP3A4-humanized mice. Elacridar coadministration did not influence cabazitaxel plasma exposure. The brain-to-plasma ratio of cabazitaxel was not increased in the ritonavir group, 7.3-fold in the elacridar group and 13.4-fold in the combined booster group in wild-type mice. This was 0.4-, 4.6- and 3.6-fold in CYP3A4-humanized mice, illustrating that Abcb1 limited cabazitaxel brain exposure also during ritonavir boosting. Ritonavir itself was also a potent substrate for the Abcb1 efflux transporter, limiting its oral availability (3.3-fold) and brain penetration (10.6-fold). Both processes were fully reversed by elacridar. The tissue disposition of ritonavir-boosted oral cabazitaxel could thus be markedly enhanced by elacridar coadministration without affecting the plasma exposure. 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7.399884 |