Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors (2024)

Kahma, H., Paludetto, M.-N., Neuvonen, M., Kurkela, M., Filppula, A. M., Niemi, M. (2024). Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors. European Journal of Pharmaceutical Sciences, 198, Artikel 106735. https://doi.org/10.1016/j.ejps.2024.106735

Kahma, Helinä ; Paludetto, Marie-Noëlle ; Neuvonen, Mikko et al. / Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors. I: European Journal of Pharmaceutical Sciences. 2024 ; Vol. 198.

@article{18342020eb9f465db3ad879e2da40618,

title = "Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors",

abstract = "Time-dependent inhibition of cytochrome P450 (CYP) enzymes has been observed for a few glucuronide metabolites of clinically used drugs. Here, we investigated the inhibitory potential of 16 glucuronide metabolites towards nine major CYP enzymes in vitro. Automated substrate co*cktail methods were used to screen time-dependent inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2 and 3A in human liver microsomes. Seven glucuronides (carvedilol β-D-glucuronide, diclofenac acyl-β-D-glucuronide, 4-hydroxyduloxetine β-D-glucuronide, ezetimibe phenoxy-β-D-glucuronide, raloxifene 4′-glucuronide, repaglinide acyl-β-D-glucuronide and valproic acid β-D-glucuronide) caused NADPH- and time-dependent inhibition of at least one of the CYPs investigated, including CYP2A6, CYP2C19 and CYP3A. In more detailed experiments, we focused on the glucuronides of carvedilol and diclofenac, which inhibited CYP3A. Carvedilol β-D-glucuronide showed weak time-dependent inhibition of CYP3A, but the parent drug carvedilol was found to be a more potent inhibitor of CYP3A, with the half-maximal inhibitor concentration (IC50) decreasing from 7.0 to 1.1 µM after a 30-min preincubation with NADPH. The maximal inactivation constant (kinact) and the inhibitor concentration causing half of kinact (KI) for CYP3A inactivation by carvedilol were 0.051 1/min and 1.8 µM, respectively. Diclofenac acyl-β-D-glucuronide caused time-dependent inactivation of CYP3A at high concentrations, with a 4-fold IC50 shift (from 400 to 98 µM after a 30-min preincubation with NADPH) and KI and kinact values of >2,000 µM and >0.16 1/min. In static predictions, carvedilol caused significant (>1.25-fold) increase in the exposure of the CYP3A substrates midazolam and simvastatin. In conclusion, we identified several glucuronide metabolites with CYP inhibitory properties. Based on detailed experiments, the inactivation of CYP3A by carvedilol may cause clinically significant drug-drug interactions.",

keywords = "CYP3A, Cytochrome P450, Glucuronide metabolites, In vitro-in vivo predictions, Metabolic drug-drug interactions, Substrate co*cktail, Time-dependent inhibition, 317 Pharmacy",

author = "Helin{\"a} Kahma and Marie-No{\"e}lle Paludetto and Mikko Neuvonen and Mika Kurkela and Filppula, {Anne M.} and Mikko Niemi and Backman, {Janne T.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = jul,

day = "1",

doi = "10.1016/j.ejps.2024.106735",

language = "English",

volume = "198",

journal = "European Journal of Pharmaceutical Sciences",

issn = "0928-0987",

publisher = "Elsevier Scientific Publ. Co",

}

Kahma, H, Paludetto, M-N, Neuvonen, M, Kurkela, M, Filppula, AM, Niemi, M 2024, 'Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors', European Journal of Pharmaceutical Sciences, vol. 198, 106735. https://doi.org/10.1016/j.ejps.2024.106735

Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors. / Kahma, Helinä; Paludetto, Marie-Noëlle; Neuvonen, Mikko et al.
I: European Journal of Pharmaceutical Sciences, Vol. 198, 106735, 01.07.2024.

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

TY - JOUR

T1 - Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors

AU - Kahma, Helinä

AU - Paludetto, Marie-Noëlle

AU - Neuvonen, Mikko

AU - Kurkela, Mika

AU - Filppula, Anne M.

AU - Niemi, Mikko

AU - Backman, Janne T.

N1 - Publisher Copyright:© 2024 The Authors

PY - 2024/7/1

Y1 - 2024/7/1

N2 - Time-dependent inhibition of cytochrome P450 (CYP) enzymes has been observed for a few glucuronide metabolites of clinically used drugs. Here, we investigated the inhibitory potential of 16 glucuronide metabolites towards nine major CYP enzymes in vitro. Automated substrate co*cktail methods were used to screen time-dependent inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2 and 3A in human liver microsomes. Seven glucuronides (carvedilol β-D-glucuronide, diclofenac acyl-β-D-glucuronide, 4-hydroxyduloxetine β-D-glucuronide, ezetimibe phenoxy-β-D-glucuronide, raloxifene 4′-glucuronide, repaglinide acyl-β-D-glucuronide and valproic acid β-D-glucuronide) caused NADPH- and time-dependent inhibition of at least one of the CYPs investigated, including CYP2A6, CYP2C19 and CYP3A. In more detailed experiments, we focused on the glucuronides of carvedilol and diclofenac, which inhibited CYP3A. Carvedilol β-D-glucuronide showed weak time-dependent inhibition of CYP3A, but the parent drug carvedilol was found to be a more potent inhibitor of CYP3A, with the half-maximal inhibitor concentration (IC50) decreasing from 7.0 to 1.1 µM after a 30-min preincubation with NADPH. The maximal inactivation constant (kinact) and the inhibitor concentration causing half of kinact (KI) for CYP3A inactivation by carvedilol were 0.051 1/min and 1.8 µM, respectively. Diclofenac acyl-β-D-glucuronide caused time-dependent inactivation of CYP3A at high concentrations, with a 4-fold IC50 shift (from 400 to 98 µM after a 30-min preincubation with NADPH) and KI and kinact values of >2,000 µM and >0.16 1/min. In static predictions, carvedilol caused significant (>1.25-fold) increase in the exposure of the CYP3A substrates midazolam and simvastatin. In conclusion, we identified several glucuronide metabolites with CYP inhibitory properties. Based on detailed experiments, the inactivation of CYP3A by carvedilol may cause clinically significant drug-drug interactions.

AB - Time-dependent inhibition of cytochrome P450 (CYP) enzymes has been observed for a few glucuronide metabolites of clinically used drugs. Here, we investigated the inhibitory potential of 16 glucuronide metabolites towards nine major CYP enzymes in vitro. Automated substrate co*cktail methods were used to screen time-dependent inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2 and 3A in human liver microsomes. Seven glucuronides (carvedilol β-D-glucuronide, diclofenac acyl-β-D-glucuronide, 4-hydroxyduloxetine β-D-glucuronide, ezetimibe phenoxy-β-D-glucuronide, raloxifene 4′-glucuronide, repaglinide acyl-β-D-glucuronide and valproic acid β-D-glucuronide) caused NADPH- and time-dependent inhibition of at least one of the CYPs investigated, including CYP2A6, CYP2C19 and CYP3A. In more detailed experiments, we focused on the glucuronides of carvedilol and diclofenac, which inhibited CYP3A. Carvedilol β-D-glucuronide showed weak time-dependent inhibition of CYP3A, but the parent drug carvedilol was found to be a more potent inhibitor of CYP3A, with the half-maximal inhibitor concentration (IC50) decreasing from 7.0 to 1.1 µM after a 30-min preincubation with NADPH. The maximal inactivation constant (kinact) and the inhibitor concentration causing half of kinact (KI) for CYP3A inactivation by carvedilol were 0.051 1/min and 1.8 µM, respectively. Diclofenac acyl-β-D-glucuronide caused time-dependent inactivation of CYP3A at high concentrations, with a 4-fold IC50 shift (from 400 to 98 µM after a 30-min preincubation with NADPH) and KI and kinact values of >2,000 µM and >0.16 1/min. In static predictions, carvedilol caused significant (>1.25-fold) increase in the exposure of the CYP3A substrates midazolam and simvastatin. In conclusion, we identified several glucuronide metabolites with CYP inhibitory properties. Based on detailed experiments, the inactivation of CYP3A by carvedilol may cause clinically significant drug-drug interactions.

KW - CYP3A

KW - Cytochrome P450

KW - Glucuronide metabolites

KW - In vitro-in vivo predictions

KW - Metabolic drug-drug interactions

KW - Substrate co*cktail

KW - Time-dependent inhibition

KW - 317 Pharmacy

U2 - 10.1016/j.ejps.2024.106735

DO - 10.1016/j.ejps.2024.106735

M3 - Article

C2 - 38423227

AN - SCOPUS:85193637622

SN - 0928-0987

VL - 198

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

M1 - 106735

ER -

Kahma H, Paludetto MN, Neuvonen M, Kurkela M, Filppula AM, Niemi M et al. Screening of 16 major drug glucuronides for time-dependent inhibition of nine drug-metabolizing CYP enzymes – detailed studies on CYP3A inhibitors. European Journal of Pharmaceutical Sciences. 2024 juli 1;198:106735. doi: 10.1016/j.ejps.2024.106735