TY - JOUR
T1 - Dual kinetics of OATP2B1
T2 - Inhibitory potency and pH-dependence of OATP2B1 inhibitors
AU - Sato, Ryo
AU - Akiyoshi, Takeshi
AU - Morita, Tokio
AU - Katayama, Kazuhiro
AU - Yajima, Kodai
AU - Kataoka, Hiroki
AU - Imaoka, Ayuko
AU - Ohtani, Hisakazu
N1 - Funding Information:
This study was supported in part by the Japan Research Foundation for JSPS Kakenhi , Grant Numbers 19K07173 [to T.A.] and 18K06758 [to H·O.]
Publisher Copyright:
© 2021 The Japanese Society for the Study of Xenobiotics
PY - 2021/12
Y1 - 2021/12
N2 - Organic anion transporting polypeptide (OATP) 2B1 is expressed in the intestine and liver, and OATP2B1-mediated transport of estrone 3-sulfate is pH-dependent and consists of: the high-affinity component (Hc) and low-affinity component (Lc). This study aimed to evaluate the influence of pH on the transport kinetics of each component, along with the inhibitory nature of ten OATP2B1 inhibitors. The Michaelis constants (Km) were 4-fold and 1.5-fold lower at pH 6.3 than at pH 7.4, for Hc and Lc respectively. The inhibitory potencies of diclofenac, indomethacin, and ibuprofen towards Hc were 1.5–4.3 fold lower at pH 6.3 than at pH 7.4. Contrastingly, inhibitory potencies towards Lc were 9.0–52 fold lower at pH 7.4. Similarly, the inhibitory effect of naproxen was stronger towards Hc at pH 6.3 and towards Lc at pH 7.4. On the other hand, celecoxib selectively inhibited Lc transport at pH 7.4. Rifampicin inhibited both components at pH 6.3 and 7.4 to a similar extent, while bromosulphophthalein, naringin, and gefitinib selectively inhibited Hc irrespective of pH. Fexofenadine inhibited neither component. In conclusion, the transport affinities of both Hc and Lc were enhanced under acidic conditions. The influence of pH on the inhibitory potency towards each component varied among the inhibitors.
AB - Organic anion transporting polypeptide (OATP) 2B1 is expressed in the intestine and liver, and OATP2B1-mediated transport of estrone 3-sulfate is pH-dependent and consists of: the high-affinity component (Hc) and low-affinity component (Lc). This study aimed to evaluate the influence of pH on the transport kinetics of each component, along with the inhibitory nature of ten OATP2B1 inhibitors. The Michaelis constants (Km) were 4-fold and 1.5-fold lower at pH 6.3 than at pH 7.4, for Hc and Lc respectively. The inhibitory potencies of diclofenac, indomethacin, and ibuprofen towards Hc were 1.5–4.3 fold lower at pH 6.3 than at pH 7.4. Contrastingly, inhibitory potencies towards Lc were 9.0–52 fold lower at pH 7.4. Similarly, the inhibitory effect of naproxen was stronger towards Hc at pH 6.3 and towards Lc at pH 7.4. On the other hand, celecoxib selectively inhibited Lc transport at pH 7.4. Rifampicin inhibited both components at pH 6.3 and 7.4 to a similar extent, while bromosulphophthalein, naringin, and gefitinib selectively inhibited Hc irrespective of pH. Fexofenadine inhibited neither component. In conclusion, the transport affinities of both Hc and Lc were enhanced under acidic conditions. The influence of pH on the inhibitory potency towards each component varied among the inhibitors.
KW - Bimodal kinetics
KW - Drug-drug interaction
KW - High- and low-affinity components
KW - NSAIDs
KW - OATP2B1
KW - pH-dependent
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U2 - 10.1016/j.dmpk.2021.100416
DO - 10.1016/j.dmpk.2021.100416
M3 - Article
C2 - 34619547
AN - SCOPUS:85116329643
SN - 1347-4367
VL - 41
JO - Drug Metabolism And Pharmacokinetics
JF - Drug Metabolism And Pharmacokinetics
M1 - 100416
ER -