title: A four-compartment PBPK heart model accounting for cardiac metabolism - model development and application.
abstract: In the field of cardiac drug efficacy and safety assessment, information on drug concentration in heart tissue is desirable. Because measuring drug concentrations in human cardiac tissue is challenging in healthy volunteers, mathematical models are used to cope with such limitations. With a goal of predicting drug concentration in cardiac tissue, we have developed a whole-body PBPK model consisting of seventeen perfusion-limited compartments. The proposed PBPK heart model consisted of four compartments: the epicardium, midmyocardium, endocardium, and pericardial fluid, and accounted for cardiac metabolism using CYP450. The model was written in R. The plasma:tissues partition coefficients (Kp) were calculated in Simcyp Simulator. The model was fitted to the concentrations of amitriptyline in plasma and the heart. The estimated parameters were as follows: 0.80 for the absorption rate [h-1], 52.6 for Kprest, 0.01 for the blood flow through the pericardial fluid [L/h], and 0.78 for the P-parameter describing the diffusion between the pericardial fluid and epicardium [L/h]. The total cardiac clearance of amitriptyline was calculated as 0.316 L/h. Although the model needs further improvement, the results support its feasibility, and it is a first attempt to provide an active drug concentration in various locations within heart tissue using a PBPK approach.
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Cracow, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Tylutki
authors.affiliation: Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Cracow, Poland.|Simcyp (a Certara Company) Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Polak
mesh_terms: D000639:Amitriptyline / Q000378:metabolism* / Q000493:pharmacokinetics; D021983:Cyclophilins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D014018:Tissue Distribution; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D000639:Amitriptyline; D021983:Cyclophilins; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D