PMID- 37429730
OWN - NLM
STAT- MEDLINE
DCOM- 20230918
LR  - 20240313
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 51
IP  - 10
DP  - 2023 Oct
TI  - Dissecting Parameters Contributing to the Underprediction of Aldehyde 
      Oxidase-Mediated Metabolic Clearance of Drugs.
PG  - 1362-1371
LID - 10.1124/dmd.123.001379 [doi]
AB  - We investigated the effect of variability and instability in aldehyde oxidase 
      (AO) content and activity on the scaling of in vitro metabolism data. AO content 
      and activity in human liver cytosol (HLC) and five recombinant human AO 
      preparations (rAO) were determined using targeted proteomics and carbazeran 
      oxidation assay, respectively. AO content was highly variable as indicated by the 
      relative expression factor (REF; i.e., HLC to rAO content) ranging from 0.001 to 
      1.7 across different in vitro systems. The activity of AO in HLC degrades at a 
      10-fold higher rate in the presence of the substrate as compared with the 
      activity performed after preincubation without substrate. To scale the metabolic 
      activity from rAO to HLC, a protein-normalized activity factor (pnAF) was 
      proposed wherein the activity was corrected by AO content, which revealed up to 
      sixfold higher AO activity in HLC versus rAO systems. A similar value of pnAF was 
      observed for another substrate, ripasudil. Physiologically based pharmacokinetic 
      (PBPK) modeling revealed a significant additional clearance (CL; 66%), which 
      allowed for the successful prediction of in vivo CL of four other substrates, 
      i.e., O-benzyl guanine, BIBX1382, zaleplon, and zoniporide. For carbazeran, the 
      metabolite identification study showed that the direct glucuronidation may be 
      contributing to around 12% elimination. Taken together, this study identified 
      differential protein content, instability of in vitro activity, role of 
      additional AO clearance, and unaccounted metabolic pathways as plausible reasons 
      for the underprediction of AO-mediated drug metabolism. Consideration of these 
      factors and integration of REF and pnAF in PBPK models will allow better 
      prediction of AO metabolism. SIGNIFICANCE STATEMENT: This study elucidated the 
      plausible reasons for the underprediction of aldehyde oxidase (AO)-mediated drug 
      metabolism and provided recommendations to address them. It demonstrated that 
      integrating protein content and activity differences and accounting for the loss 
      of AO activity, as well as consideration of extrahepatic clearance and additional 
      pathways, would improve the in vitro to in vivo extrapolation of AO-mediated drug 
      metabolism using physiologically based pharmacokinetic modeling.
CI  - Copyright (c) 2023 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Subash, Sandhya
AU  - Subash S
AUID- ORCID: 0009-0000-4001-7534
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Singh, Dilip K
AU  - Singh DK
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Ahire, Deepak S
AU  - Ahire DS
AUID- ORCID: 0000-0001-8537-6047
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Khojasteh, S Cyrus
AU  - Khojasteh SC
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Murray, Bernard P
AU  - Murray BP
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Zientek, Michael A
AU  - Zientek MA
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Jones, Robert S
AU  - Jones RS
AUID- ORCID: 0000-0002-5283-8070
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Kulkarni, Priyanka
AU  - Kulkarni P
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Smith, Bill J
AU  - Smith BJ
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Heyward, Scott
AU  - Heyward S
AUID- ORCID: 0000-0001-7805-3522
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Cronin, Ciaran N
AU  - Cronin CN
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.).
FAU - Prasad, Bhagwat
AU  - Prasad B
AUID- ORCID: 0000-0002-9090-0912
AD  - Department of Pharmaceutical Sciences, Washington State University (WSU), 
      Spokane, Washington (S.S., D.K.S., D.S.A., B.P.); Drug Metabolism and 
      Pharmacokinetics, Genentech Inc., South San Francisco, California (S.C.K., 
      R.S.J.); Drug Metabolism, Gilead Sciences, Foster City, California (B.P.M., 
      B.J.S.); Drug Metabolism and Pharmacokinetics, Takeda Development Center 
      Americas, San Diego, California (M.A.Z.); Drug Metabolism and Pharmacokinetics, 
      Takeda Development Center Americas, Cambridge, Massachusetts (P.K.); BioIVT Inc., 
      Baltimore, Maryland (S.H.); and Structural Biology and Protein Sciences, Pfizer 
      Global Research & Development and Medical, La Jolla, California (C.N.C.) 
      bhagwat.prasad@wsu.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230710
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0N4I6K95P2 (carbazeran)
RN  - EC 1.2.3.1 (Aldehyde Oxidase)
RN  - 0 (Carbamates)
SB  - IM
EIN - Drug Metab Dispos. 2024 Mar 13;52(4):322. PMID: 38479790
MH  - Humans
MH  - *Aldehyde Oxidase/metabolism
MH  - *Carbamates/metabolism
MH  - Kinetics
MH  - Metabolic Clearance Rate
MH  - Liver/metabolism
EDAT- 2023/07/11 01:07
MHDA- 2023/09/18 12:42
CRDT- 2023/07/10 21:37
PHST- 2023/04/27 00:00 [received]
PHST- 2023/07/07 00:00 [accepted]
PHST- 2023/09/18 12:42 [medline]
PHST- 2023/07/11 01:07 [pubmed]
PHST- 2023/07/10 21:37 [entrez]
AID - dmd.123.001379 [pii]
AID - 10.1124/dmd.123.001379 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2023 Oct;51(10):1362-1371. doi: 10.1124/dmd.123.001379. Epub 
      2023 Jul 10.