A mathematical model of the kinetics of 5-fluorouracil and its catabolites in freshly isolated rat hepatocytes

France Mentre; Jean Louis Steimer; Jean Pierre Sommadossi; Robert B. Diasio; Jean Paul Cano

doi:10.1016/0006-2952(84)90688-9

A mathematical model of the kinetics of 5-fluorouracil and its catabolites in freshly isolated rat hepatocytes

France Mentre, Jean Louis Steimer, Jean Pierre Sommadossi, Robert B. Diasio, Jean Paul Cano

Pharmacology

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

A mathematical model for the kinetics of 5-fluorouracil (FUra) catabolism in liver cells is proposed. It is based on published data for the metabolism of FUra by isolated rat hepatocytes. The model relies on biochemical knowledge of the catabolic pathway. The key-steps are: (i) the cellular uptake and the conversion of the unchanged drug to dihydrofluorouracil (FUH₂) and subsequently to α-fluoro-β-alanine (FBAL); (ii) the cellular fluxes of the 2 catabolites, FUH₂ and FBAL. Water is partitioned between the extracellular and intracellular spaces. The first step is described by Michaelis-Menten kinetics and the other processes by first-order kinetics. Satisfactory fitting of the model validates these simplifications and provides values for the parameters describing the process. The model indicates that (i) the kinetics of FUra disappearance are non linear, the V_max of the first step being between 3.1 and 5.0 μM/min and the K_m between 12 and 37 μM; (ii) the rate limiting step is the degradation of FUH₂ (the major intracellular catabolite) with a rate constant of 0.1 to 0.02 min^-1; (iii) the FUH₂ trasmembrane exchange is active; (iv) the exchange of the final catabolite FBAL is by diffusion.

Original language	English (US)
Pages (from-to)	2727-2732
Number of pages	6
Journal	Biochemical Pharmacology
Volume	33
Issue number	17
DOIs	https://doi.org/10.1016/0006-2952(84)90688-9
State	Published - Sep 1 1984

ASJC Scopus subject areas

Biochemistry
Pharmacology

Access to Document

10.1016/0006-2952(84)90688-9

Cite this

@article{02c69d816c0b45f283c55352f1d15afb,

title = "A mathematical model of the kinetics of 5-fluorouracil and its catabolites in freshly isolated rat hepatocytes",

abstract = "A mathematical model for the kinetics of 5-fluorouracil (FUra) catabolism in liver cells is proposed. It is based on published data for the metabolism of FUra by isolated rat hepatocytes. The model relies on biochemical knowledge of the catabolic pathway. The key-steps are: (i) the cellular uptake and the conversion of the unchanged drug to dihydrofluorouracil (FUH2) and subsequently to α-fluoro-β-alanine (FBAL); (ii) the cellular fluxes of the 2 catabolites, FUH2 and FBAL. Water is partitioned between the extracellular and intracellular spaces. The first step is described by Michaelis-Menten kinetics and the other processes by first-order kinetics. Satisfactory fitting of the model validates these simplifications and provides values for the parameters describing the process. The model indicates that (i) the kinetics of FUra disappearance are non linear, the Vmax of the first step being between 3.1 and 5.0 μM/min and the Km between 12 and 37 μM; (ii) the rate limiting step is the degradation of FUH2 (the major intracellular catabolite) with a rate constant of 0.1 to 0.02 min-1; (iii) the FUH2 trasmembrane exchange is active; (iv) the exchange of the final catabolite FBAL is by diffusion.",

author = "France Mentre and Steimer, {Jean Louis} and Sommadossi, {Jean Pierre} and Diasio, {Robert B.} and Cano, {Jean Paul}",

note = "Funding Information: Acknowledgements---Farecece sst o the VAX computer of the {"}Serviced 'InformatiquMe6 dicale{"}( CHU Piti6-Salp6tri6reA, ssistancPeu bliqued esH 6pitauxd eP aris)i s gratefullayc knowledgeTdh. is work wasp artlys upported by a grantf romt he{"} CaisseM utuelleP rovincialdee sP ro-fessionsli b6ralesb{"} y INSERM GrantN o. 119017u nder the INSERM-NCI (France-U.S.Ab) y a grantf rom the {"}Associatiopno url e d6veloppemednet la Recherchseu r le Cancer{"}a ndG rantC A-23412.",

year = "1984",

month = sep,

day = "1",

doi = "10.1016/0006-2952(84)90688-9",

language = "English (US)",

volume = "33",

pages = "2727--2732",

journal = "Biochemical Pharmacology",

issn = "0006-2952",

publisher = "Elsevier Inc.",

number = "17",

}

TY - JOUR

T1 - A mathematical model of the kinetics of 5-fluorouracil and its catabolites in freshly isolated rat hepatocytes

AU - Mentre, France

AU - Steimer, Jean Louis

AU - Sommadossi, Jean Pierre

AU - Diasio, Robert B.

AU - Cano, Jean Paul

N1 - Funding Information: Acknowledgements---Farecece sst o the VAX computer of the "Serviced 'InformatiquMe6 dicale"( CHU Piti6-Salp6tri6reA, ssistancPeu bliqued esH 6pitauxd eP aris)i s gratefullayc knowledgeTdh. is work wasp artlys upported by a grantf romt he" CaisseM utuelleP rovincialdee sP ro-fessionsli b6ralesb" y INSERM GrantN o. 119017u nder the INSERM-NCI (France-U.S.Ab) y a grantf rom the "Associatiopno url e d6veloppemednet la Recherchseu r le Cancer"a ndG rantC A-23412.

PY - 1984/9/1

Y1 - 1984/9/1

N2 - A mathematical model for the kinetics of 5-fluorouracil (FUra) catabolism in liver cells is proposed. It is based on published data for the metabolism of FUra by isolated rat hepatocytes. The model relies on biochemical knowledge of the catabolic pathway. The key-steps are: (i) the cellular uptake and the conversion of the unchanged drug to dihydrofluorouracil (FUH2) and subsequently to α-fluoro-β-alanine (FBAL); (ii) the cellular fluxes of the 2 catabolites, FUH2 and FBAL. Water is partitioned between the extracellular and intracellular spaces. The first step is described by Michaelis-Menten kinetics and the other processes by first-order kinetics. Satisfactory fitting of the model validates these simplifications and provides values for the parameters describing the process. The model indicates that (i) the kinetics of FUra disappearance are non linear, the Vmax of the first step being between 3.1 and 5.0 μM/min and the Km between 12 and 37 μM; (ii) the rate limiting step is the degradation of FUH2 (the major intracellular catabolite) with a rate constant of 0.1 to 0.02 min-1; (iii) the FUH2 trasmembrane exchange is active; (iv) the exchange of the final catabolite FBAL is by diffusion.

AB - A mathematical model for the kinetics of 5-fluorouracil (FUra) catabolism in liver cells is proposed. It is based on published data for the metabolism of FUra by isolated rat hepatocytes. The model relies on biochemical knowledge of the catabolic pathway. The key-steps are: (i) the cellular uptake and the conversion of the unchanged drug to dihydrofluorouracil (FUH2) and subsequently to α-fluoro-β-alanine (FBAL); (ii) the cellular fluxes of the 2 catabolites, FUH2 and FBAL. Water is partitioned between the extracellular and intracellular spaces. The first step is described by Michaelis-Menten kinetics and the other processes by first-order kinetics. Satisfactory fitting of the model validates these simplifications and provides values for the parameters describing the process. The model indicates that (i) the kinetics of FUra disappearance are non linear, the Vmax of the first step being between 3.1 and 5.0 μM/min and the Km between 12 and 37 μM; (ii) the rate limiting step is the degradation of FUH2 (the major intracellular catabolite) with a rate constant of 0.1 to 0.02 min-1; (iii) the FUH2 trasmembrane exchange is active; (iv) the exchange of the final catabolite FBAL is by diffusion.

UR - http://www.scopus.com/inward/record.url?scp=0021149420&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021149420&partnerID=8YFLogxK

U2 - 10.1016/0006-2952(84)90688-9

DO - 10.1016/0006-2952(84)90688-9

M3 - Article

C2 - 6431993

AN - SCOPUS:0021149420

SN - 0006-2952

VL - 33

SP - 2727

EP - 2732

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

IS - 17

ER -

A mathematical model of the kinetics of 5-fluorouracil and its catabolites in freshly isolated rat hepatocytes

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this