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Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib.
- Source :
-
Pharmaceutics [Pharmaceutics] 2020 Aug 20; Vol. 12 (9). Date of Electronic Publication: 2020 Aug 20. - Publication Year :
- 2020
-
Abstract
- Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200-800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2-15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC <subscript>0-12 h</subscript> ) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC <subscript>0-12 h</subscript> decreased by 27% (90% CI: -38% to -14%; P < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib- N -oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.
Details
- Language :
- English
- ISSN :
- 1999-4923
- Volume :
- 12
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 32825359
- Full Text :
- https://doi.org/10.3390/pharmaceutics12090788