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

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 AUC0-120 min of DM1 in Oatp1a/b-/- was 1.9-fold (p < 0.05) higher than that in wild-type mice, and that of docetaxel was 2.4-fold (p < 0.05) higher. We further observed impaired hepatic uptake and intestinal disposition for DM1 and docetaxel in the Oatp-ablated strains. None of these parameters showed rescue by the OATP1B1 or -1B3 transporters in the humanized mouse strains, suggesting a minimal role of OATP1B1/1B3. Ritonavir itself was also a potent substrate for mOatp1a/b, showing a 2.9-fold (p < 0.0001) increased plasma AUC0-120 min and 3.5-fold (p < 0.0001) decreased liver-to-plasma ratio in Oatp1a/b-/- compared to those in wild-type mice. Furthermore, we observed the tight binding of cabazitaxel and its active metabolites, including docetaxel, to plasma carboxylesterase (Ces1c) in mice, which may complicate the interpretation of pharmacokinetic and pharmacodynamic mouse studies. Collectively, these results will help to further optimize (pre)clinical research into the safety and efficacy of orally applied cabazitaxel.

Medienart:

E-Artikel

Erscheinungsjahr:

2024

Erschienen:

2024

Enthalten in:

Zur Gesamtaufnahme - volume:21

Enthalten in:

Molecular pharmaceutics - 21(2024), 4 vom: 01. Apr., Seite 1952-1964

Sprache:

Englisch

Beteiligte Personen:

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

Links:

Volltext

Themen:

15H5577CQD
51F690397J
Cabazitaxel
Cabazitaxel/jevtana
Carboxylesterase
Carboxylesterase (Ces1)
Cytochrome P450 3A (CYP3A4)
Docetaxel
EC 3.1.1.1
Journal Article
Liver-Specific Organic Anion Transporter 1
O3J8G9O825
Organic Anion Transporters
Organic Anion Transporters, Sodium-Independent
Organic anion-transporting polypeptides (OATPs)
Pharmacokinetics
Ritonavir
Solute Carrier Organic Anion Transporter Family Member 1B3
Taxoids

Anmerkungen:

Date Completed 03.04.2024

Date Revised 04.04.2024

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1021/acs.molpharmaceut.3c01205

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM369136896