P-gp and BCRP inhibitors were identified in all physicochemical property categories, with the exception that no BCRP inhibitor had a LogP <1.0. P-gp inhibitors tended to be highly permeable and lipophilic, with a higher proportion of compounds with high lipophilicity (LogP >4.0, LogD >2.5) being inhibitors. For BCRP, relatively large compounds with MW ≥500, medium to high permeability and with intermediate-high lipophilicity were more likely to be inhibitors. Compounds in all ionisation states except zwitterions were BCRP inhibitors, but no association of ionisation state with P-gp inhibition could be identified in this small dataset except for zwitterions being P-gp inhibitors.
OATP1B1 and OATP1B3 inhibitors were identified in all physicochemical property categories. Intermediate-high lipophilicity (LogD >0.5 and/or LogP >1.0), acidic and relatively large size (MW ≥ 500 Da) compounds tended to be inhibitors. No OATP1B1 or OATP1B3 inhibitor had a LogP <1.0. Additionally, neutral compounds were more likely to be OATP1B1 inhibitors. The tendency to inhibit OATP1B1 also included compounds with medium to high permeability, whilst compounds with medium permeability were identified as OATP1B3 inhibitors.
OCT1, OCT2, MATE1, MATE2-K inhibitors were also identified in all physicochemical property categories. Physicochemical property analysis was not conducted for MATE1 due to the low number of non-inhibitors (n=2). Bases were associated with OCT1 and MATE2-K inhibitors. Additionally, high lipophilicity, high permeability, and neutral compounds tended to be OCT1 inhibitors and compounds with intermediate lipophilicity were likely to be MATE2-K inhibitors. In this dataset, there were no physicochemical property trends identified for OCT2 inhibition.
OAT3 and OAT1 inhibitors were also identified in most physicochemical categories. Higher proportion of acidic compounds were OAT1 and OAT3 inhibitors while the majority of the compounds in other ionisation states were non-inhibitors.
Substrates:
Compounds with intermediate-high lipophilicity were likely to be P-gp and/or BCRP substrates. Although, substrates of both transporters were identified in all ionisation states, neutral and basic compounds were predominantly substrates for both transporters.
For OAT3, smaller compounds (< 500 Da) tended to be substrates while high lipophilicity compounds were mostly non-substrates. Contrary to expectations, no acids in this dataset were OATP1B1 and/or OATP1B3 substrates. Physicochemical property analyses of substrates of the other transporters (OAT1, OCT1, OCT2, MATE1 and MATE2-K) could not be conducted due to limited dataset.
OATP1B1 and OATP1B3 inhibitors were identified in all physicochemical property categories. Intermediate-high lipophilicity (LogD >0.5 and/or LogP >1.0), acidic and relatively large size (MW ≥ 500 Da) compounds tended to be inhibitors. No OATP1B1 or OATP1B3 inhibitor had a LogP <1.0. Additionally, neutral compounds were more likely to be OATP1B1 inhibitors. The tendency to inhibit OATP1B1 also included compounds with medium to high permeability, whilst compounds with medium permeability were identified as OATP1B3 inhibitors.
OCT1, OCT2, MATE1, MATE2-K inhibitors were also identified in all physicochemical property categories. Physicochemical property analysis was not conducted for MATE1 due to the low number of non-inhibitors (n=2). Bases were associated with OCT1 and MATE2-K inhibitors. Additionally, high lipophilicity, high permeability, and neutral compounds tended to be OCT1 inhibitors and compounds with intermediate lipophilicity were likely to be MATE2-K inhibitors. In this dataset, there were no physicochemical property trends identified for OCT2 inhibition.
OAT3 and OAT1 inhibitors were also identified in most physicochemical categories. Higher proportion of acidic compounds were OAT1 and OAT3 inhibitors while the majority of the compounds in other ionisation states were non-inhibitors.
Substrates:
Compounds with intermediate-high lipophilicity were likely to be P-gp and/or BCRP substrates. Although, substrates of both transporters were identified in all ionisation states, neutral and basic compounds were predominantly substrates for both transporters.
For OAT3, smaller compounds (< 500 Da) tended to be substrates while high lipophilicity compounds were mostly non-substrates. Contrary to expectations, no acids in this dataset were OATP1B1 and/or OATP1B3 substrates. Physicochemical property analyses of substrates of the other transporters (OAT1, OCT1, OCT2, MATE1 and MATE2-K) could not be conducted due to limited dataset.
