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Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion Protein‐Mediated Drug‐Drug Interactions in Healthy Volunteers
Author(s) -
Miyake Takeshi,
Kimoto Emi,
Luo Lina,
Mathialagan Sumathy,
Horlbogen Lauren M.,
Ramanathan Ragu,
Wood Linda S.,
Johnson Jillian G.,
Le Vu H.,
Vourvahis Manoli,
Rodrigues A. David,
Muto Chieko,
Furihata Kenichi,
Sugiyama Yuichi,
Kusuhara Hiroyuki
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2022
Subject(s) - biomarker , pharmacology , pyrimethamine , creatinine , drug , renal function , medicine , metformin , urine , chemistry , chloroquine , immunology , biochemistry , malaria , insulin
Endogenous biomarkers are emerging to advance clinical drug‐drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2‐K‐mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2‐K. In addition to the previously reported endogenous biomarker candidates (creatinine and N 1 ‐methylnicotinamide (1‐NMN)), N 1 ‐methyladenosine (m 1 A) was included as novel biomarkers. 1‐NMN and m 1 A presented as superior MATE1/2‐K biomarkers since changes in their renal clearance (CL r ) along with pyrimethamine dose were well‐correlated with metformin CL r changes. The CL r of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CL r changes. Nonlinear regression analysis (CL r vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant ( K i ) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo K i value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro K i for MATE1 (1‐NMN) and MATE2‐K (1‐NMN and m 1 A). It is concluded that 1‐NMN and m 1 A CL r can be leveraged as quantitative MATE1/2‐K biomarkers for DDI risk assessment in healthy volunteers.