Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters
(1) Background: Hydroxychloroquine is used to treat malaria and autoimmune diseases, and its potential use against COVID-19 is currently under investigation. Thus far, information on interactions of hydroxychloroquine with drug transporters mediating drug-drug interactions is limited. We assessed th...
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| Format: | Article |
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MDPI AG
2020-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/10/919 |
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| author | Johanna Weiss Gzona Bajraktari-Sylejmani Walter E. Haefeli |
| author_facet | Johanna Weiss Gzona Bajraktari-Sylejmani Walter E. Haefeli |
| author_sort | Johanna Weiss |
| collection | DOAJ |
| description | (1) Background: Hydroxychloroquine is used to treat malaria and autoimmune diseases, and its potential use against COVID-19 is currently under investigation. Thus far, information on interactions of hydroxychloroquine with drug transporters mediating drug-drug interactions is limited. We assessed the inhibition of important efflux (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) and uptake transporters (organic anion transporting polypeptide (OATP)-1B1, OATP1B3, OATP2B1) by hydroxychloroquine, tested its P-gp and BCRP substrate characteristics, and evaluated the induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X (PXR) (<i>CYP3A4, ABCB1</i>) and aryl hydrocarbon receptor (AhR) (<i>CYP1A1, CYP1A2</i>). (2) Methods: Transporter inhibition was evaluated in transporter over-expressing cell lines using fluorescent probe substrates. P-gp and BCRP substrate characteristics were assessed by comparing growth inhibition of over-expressing and parental cell lines. Possible mRNA induction was analysed in LS180 cells by quantitative real-time PCR. (3) Results: Hydroxychloroquine did not inhibit BCRP or the OATPs tested but inhibited P-gp at concentrations exceeding 10 µM. P-gp overexpressing cells were 5.2-fold more resistant to hydroxychloroquine than control cells stressing its substrate characteristics. Hydroxychloroquine did not induce genes regulated by PXR or AhR. (4) Conclusions: This is the first evidence that hydroxychloroquine’s interaction potential with drug transporters is low, albeit bioavailability of simultaneously orally administered P-gp substrates might be increased by hydroxychloroquine. |
| first_indexed | 2024-03-10T16:04:11Z |
| format | Article |
| id | doaj.art-f1c725f8ec7d43cfacf8718e9bd7397e |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T16:04:11Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-f1c725f8ec7d43cfacf8718e9bd7397e2023-11-20T15:04:28ZengMDPI AGPharmaceutics1999-49232020-09-01121091910.3390/pharmaceutics12100919Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug TransportersJohanna Weiss0Gzona Bajraktari-Sylejmani1Walter E. Haefeli2Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany(1) Background: Hydroxychloroquine is used to treat malaria and autoimmune diseases, and its potential use against COVID-19 is currently under investigation. Thus far, information on interactions of hydroxychloroquine with drug transporters mediating drug-drug interactions is limited. We assessed the inhibition of important efflux (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) and uptake transporters (organic anion transporting polypeptide (OATP)-1B1, OATP1B3, OATP2B1) by hydroxychloroquine, tested its P-gp and BCRP substrate characteristics, and evaluated the induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X (PXR) (<i>CYP3A4, ABCB1</i>) and aryl hydrocarbon receptor (AhR) (<i>CYP1A1, CYP1A2</i>). (2) Methods: Transporter inhibition was evaluated in transporter over-expressing cell lines using fluorescent probe substrates. P-gp and BCRP substrate characteristics were assessed by comparing growth inhibition of over-expressing and parental cell lines. Possible mRNA induction was analysed in LS180 cells by quantitative real-time PCR. (3) Results: Hydroxychloroquine did not inhibit BCRP or the OATPs tested but inhibited P-gp at concentrations exceeding 10 µM. P-gp overexpressing cells were 5.2-fold more resistant to hydroxychloroquine than control cells stressing its substrate characteristics. Hydroxychloroquine did not induce genes regulated by PXR or AhR. (4) Conclusions: This is the first evidence that hydroxychloroquine’s interaction potential with drug transporters is low, albeit bioavailability of simultaneously orally administered P-gp substrates might be increased by hydroxychloroquine.https://www.mdpi.com/1999-4923/12/10/919hydroxychloroquinedrug-drug interactiondrug transportersinhibitioninductionP-glycoprotein |
| spellingShingle | Johanna Weiss Gzona Bajraktari-Sylejmani Walter E. Haefeli Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters Pharmaceutics hydroxychloroquine drug-drug interaction drug transporters inhibition induction P-glycoprotein |
| title | Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters |
| title_full | Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters |
| title_fullStr | Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters |
| title_full_unstemmed | Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters |
| title_short | Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters |
| title_sort | interaction of hydroxychloroquine with pharmacokinetically important drug transporters |
| topic | hydroxychloroquine drug-drug interaction drug transporters inhibition induction P-glycoprotein |
| url | https://www.mdpi.com/1999-4923/12/10/919 |
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