PMID- 31641009
OWN - NLM
STAT- MEDLINE
DCOM- 20201127
LR  - 20210101
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 48
IP  - 1
DP  - 2020 Jan
TI  - Numerical Analysis of Time-Dependent Inhibition by MDMA.
PG  - 1-7
LID - 10.1124/dmd.119.089268 [doi]
AB  - Methylenedioxymethamphetamine (MDMA) is a known drug of abuse and schedule 1 
      narcotic under the Controlled Substances Act. Previous pharmacokinetic work on 
      MDMA used classic linearization techniques to conclude irreversible 
      mechanism-based inhibition of CYP2D6. The current work challenges this outcome by 
      assessing the possibility of two alternative reversible kinetic inhibition 
      mechanisms known as the quasi-irreversible (QI) model and equilibrium model (EM). 
      In addition, progress curve experiments were used to investigate the residual 
      metabolism of MDMA by liver microsomes and CYP2D6 baculosomes over incubation 
      periods up to 30 minutes. These experiments revealed activity in a terminal 
      linear phase at the fractional rates with respect to initial turnover of 0.0354 +/- 
      0.0089 in human liver microsomes and 0.0114 +/- 0.0025 in baculosomes. Numerical 
      model fits to percentage of remaining activity (PRA) data were consistent with 
      progress curve modeling results, wherein an irreversible inhibition pathway was 
      found unnecessary for good fit scoring. Both QI and EM kinetic mechanisms fit the 
      PRA data well, although in CYP2D6 baculosomes the inclusion of an irreversible 
      inactivation pathway did not allow for convergence to a reasonable fit. The 
      kinetic complexity accessible to numerical modeling has been used to determine 
      that MDMA is not an irreversible inactivator of CYP2D6, and instead follows what 
      can be generally referred to as slowly reversible inhibition. SIGNIFICANCE 
      STATEMENT: The work herein describes the usage of computational models to 
      delineate between irreversible and slowly reversible time-dependent inhibition. 
      Such models are used in the paper to analyze MDMA and classify it as a reversible 
      time-dependent inhibitor.
CI  - Copyright (c) 2019 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Rodgers, John T
AU  - Rodgers JT
AD  - Department of Chemistry, Washington State University, Pullman, Washington.
FAU - Jones, Jeffrey P
AU  - Jones JP
AD  - Department of Chemistry, Washington State University, Pullman, Washington 
      jpj@wsu.edu.
LA  - eng
GR  - R01 GM114369/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20191022
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Cytochrome P-450 CYP2D6 Inhibitors)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Computer Simulation
MH  - Cytochrome P-450 CYP2D6/genetics/*metabolism
MH  - Cytochrome P-450 CYP2D6 Inhibitors/*pharmacokinetics
MH  - Humans
MH  - In Vitro Techniques
MH  - Metabolic Detoxication, Phase I
MH  - Metabolic Detoxication, Phase II
MH  - Microsomes, Liver/*drug effects/enzymology
MH  - *Models, Biological
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacokinetics
MH  - Time Factors
PMC - PMC6904883
EDAT- 2019/10/24 06:00
MHDA- 2020/11/28 06:00
PMCR- 2021/01/01
CRDT- 2019/10/24 06:00
PHST- 2019/09/03 00:00 [received]
PHST- 2019/10/12 00:00 [accepted]
PHST- 2019/10/24 06:00 [pubmed]
PHST- 2020/11/28 06:00 [medline]
PHST- 2019/10/24 06:00 [entrez]
PHST- 2021/01/01 00:00 [pmc-release]
AID - dmd.119.089268 [pii]
AID - DMD_089268 [pii]
AID - 10.1124/dmd.119.089268 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2020 Jan;48(1):1-7. doi: 10.1124/dmd.119.089268. Epub 2019 Oct 
      22.