Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats
A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/12/2172 |
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| author | Agnieszka Karbownik Danuta Szkutnik-Fiedler Tomasz Grabowski Anna Wolc Joanna Stanisławiak-Rudowicz Radosław Jaźwiec Edmund Grześkowiak Edyta Szałek |
| author_facet | Agnieszka Karbownik Danuta Szkutnik-Fiedler Tomasz Grabowski Anna Wolc Joanna Stanisławiak-Rudowicz Radosław Jaźwiec Edmund Grześkowiak Edyta Szałek |
| author_sort | Agnieszka Karbownik |
| collection | DOAJ |
| description | A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (I<sub>SOR+MF</sub>), sorafenib (II<sub>SOR</sub>), and morphine (III<sub>MF</sub>). Morphine caused a significant increase in maximum plasma concentrations (C<sub>max</sub>) and the area under the plasma concentration–time curves (AUC<sub>0–t</sub>, and AUC<sub>0–∞</sub>) of sorafenib by 108.3 (<i>p</i> = 0.003), 55.9 (<i>p</i> = 0.0115), and 62.7% (<i>p</i> = 0.0115), respectively. Also, the C<sub>max</sub> and AUC<sub>0–t</sub> of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (<i>p</i> = 0.0022 and <i>p</i> = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the C<sub>max</sub> of morphine (by 0.5-fold, <i>p</i> = 0.0018). Moreover, in the presence of sorafenib the C<sub>max</sub>, AUC<sub>0–t</sub>, and AUC<sub>0–∞</sub> of the morphine metabolite M3G increased by 112.62 (<i>p</i> < 0.0001), 46.82 (<i>p</i> = 0.0124), and 46.78% (<i>p</i> = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects. |
| first_indexed | 2024-03-10T03:19:55Z |
| format | Article |
| id | doaj.art-eab7ca12e6b04047a2d2383652c3f609 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T03:19:55Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-eab7ca12e6b04047a2d2383652c3f6092023-11-23T10:06:53ZengMDPI AGPharmaceutics1999-49232021-12-011312217210.3390/pharmaceutics13122172Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in RatsAgnieszka Karbownik0Danuta Szkutnik-Fiedler1Tomasz Grabowski2Anna Wolc3Joanna Stanisławiak-Rudowicz4Radosław Jaźwiec5Edmund Grześkowiak6Edyta Szałek7Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, PolandDepartment of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, PolandPreclinical Development, Polpharma Biologics SA, Trzy Lipy 3, 80-172 Gdańsk, PolandDepartment of Animal Science, Iowa State University, 239E Kildee Hall, Ames, IA 50011, USADepartment of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, PolandLaboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics PAS, Polish Academy of Sciences, 5A Pawińskiego Str., 02-106 Warsaw, PolandDepartment of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, PolandDepartment of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, 14 Św. Marii Magdaleny Str., 61-861 Poznań, PolandA combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (I<sub>SOR+MF</sub>), sorafenib (II<sub>SOR</sub>), and morphine (III<sub>MF</sub>). Morphine caused a significant increase in maximum plasma concentrations (C<sub>max</sub>) and the area under the plasma concentration–time curves (AUC<sub>0–t</sub>, and AUC<sub>0–∞</sub>) of sorafenib by 108.3 (<i>p</i> = 0.003), 55.9 (<i>p</i> = 0.0115), and 62.7% (<i>p</i> = 0.0115), respectively. Also, the C<sub>max</sub> and AUC<sub>0–t</sub> of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (<i>p</i> = 0.0022 and <i>p</i> = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the C<sub>max</sub> of morphine (by 0.5-fold, <i>p</i> = 0.0018). Moreover, in the presence of sorafenib the C<sub>max</sub>, AUC<sub>0–t</sub>, and AUC<sub>0–∞</sub> of the morphine metabolite M3G increased by 112.62 (<i>p</i> < 0.0001), 46.82 (<i>p</i> = 0.0124), and 46.78% (<i>p</i> = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.https://www.mdpi.com/1999-4923/13/12/2172pharmacokineticsdrug–drug interactionsorafenibsorafenib N-oxidemorphine |
| spellingShingle | Agnieszka Karbownik Danuta Szkutnik-Fiedler Tomasz Grabowski Anna Wolc Joanna Stanisławiak-Rudowicz Radosław Jaźwiec Edmund Grześkowiak Edyta Szałek Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats Pharmaceutics pharmacokinetics drug–drug interaction sorafenib sorafenib N-oxide morphine |
| title | Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats |
| title_full | Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats |
| title_fullStr | Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats |
| title_full_unstemmed | Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats |
| title_short | Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats |
| title_sort | pharmacokinetic drug interaction study of sorafenib and morphine in rats |
| topic | pharmacokinetics drug–drug interaction sorafenib sorafenib N-oxide morphine |
| url | https://www.mdpi.com/1999-4923/13/12/2172 |
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