title: Quantitative analysis of drug effects at the whole-body level: a case study for glucose metabolism in malaria patients.
abstract: We propose a hierarchical modelling approach to construct models for disease states at the whole-body level. Such models can simulate effects of drug-induced inhibition of reaction steps on the whole-body physiology. We illustrate the approach for glucose metabolism in malaria patients, by merging two detailed kinetic models for glucose metabolism in the parasite Plasmodium falciparum and the human red blood cell with a coarse-grained model for whole-body glucose metabolism. In addition we use a genome-scale metabolic model for the parasite to predict amino acid production profiles by the malaria parasite that can be used as a complex biomarker.
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa Molecular Cell Physiology, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands MIB, University of Manchester, M1 7EN Manchester, U.K. jls@sun.ac.za.
authors.forename: Jacky L
authors.initials: JL
authors.lastname: Snoep
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Green
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Johann
authors.initials: J
authors.lastname: Eicher
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Palm
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Gerald
authors.initials: G
authors.lastname: Penkler
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Francois
authors.initials: F
authors.lastname: du Toit
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Walters
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: Robert
authors.initials: R
authors.lastname: Burger
authors.affiliation: Molecular Cell Physiology, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands MIB, University of Manchester, M1 7EN Manchester, U.K.
authors.forename: Hans V
authors.initials: HV
authors.lastname: Westerhoff
authors.affiliation: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
authors.forename: David D
authors.initials: DD
authors.lastname: van Niekerk
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology; D005947:Glucose / Q000378:metabolism*; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism* / Q000469:parasitology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D005947:Glucose
keywords: Plasmodium falciparum; glucose metabolism; malaria; multi-scale hierarchical model