Ana Catalán-Latorre, Amparo Nácher, Virginia Merino, N. VÃctor Jiménez-Torres, Matilde Merino-Sanjuán
Pharmacy and Pharmaceutical Technology Department, University of Valencia (Spain)
Objectives: Protein-energy undernutrition (PEU) can seriously compromise the outcomes of other pathologies since pathophysiological derangements in patients with PEU have a profound impact on absorption, protein binding, metabolism and elimination of drugs1-3. Taurine is a conditionally essential aminoacid involved in numerous biological processes and its needs increase in response to pathological conditions4. The aim of this study was to perform a PK modelling to describe the behavior of taurine in well-nourished rats and analyze the influence of PEU on the PK parameters of taurine in undernourished rats.
Methods: Wistar rats were randomly distributed in two groups -WN (well-nourished) and UN (undernourished) – and were fed with different diets for 23-26 days5. During this time, weight was recorded daily and serum albumin was registered weekly. After this time taurine was administered intravenously (IV) or orally (PO) to WN and UN rats at different doses: 1, 10, and 100 mg (N=68). Plasma samples were collected for taurine and were analyzed by HPLC. Population pharmacokinetic modelling was performed using nonlinear mixed effects software (NONMEM 7.0). Several distribution and absorption models were explored in combination with dose and/or time covariate effects. Covariates such as nutritional status, serum albumin, body weight and score of undernutrition were used.
Results: A two-compartment population pharmacokinetic model with zero order endogenous formation, passive absorption, first order kinetics distribution and nonlinear elimination with parallel Michaelis-Menten excretion and reabsorption processes best described taurine pharmacokinetics. When models were scaled for malnutrition, undernutrition acted as covariate reducing the Vmax of the active elimination process. Goodness of fit plots (GOFP) showed reasonable good results. The main PK parameters are shown: ka=1.19 h-1, Velo=13,70 mg/h, Vc=0.042 l/h, K12=2.61 h-1, K21=0.73 h-1, Vmsec=192.0 mg/l∙h-1 Kmsec=399.0 mg/l, Vmreabs=16.9 mg/l∙h-1, Kmreabs=96.1 mg/l, FDNVms=0.91.
Conclusions: Data analysis showed linear absorption and distribution, and non-linear elimination processes for taurine. Elimination of taurine was reduced in undernourished animals, suggesting that the reabsorption process via the secretion transporter was modified in this group. Modelling provides a useful tool to describe the levels of taurine and offers a robust method to understand the changes in PK ocurred in undernorishment.
References:
[1] Lee JH, Suh OK, Lee MG: Pharmacokinetic changes in drugs during protein-calorie malnutrition: correlation between drug metabolism and hepatic microsomal cytochrome P450 isozymes, Arch Pharm Res 2004, 27:693-712
[2] Lykke M, Hother AL, Hansen CF, Friis H, Molgaard C, Michaelsen KF, Briend A, Larsen T, Sangild PT, Thymann T: Malnutrition induces gut atrophy and increases hepatic fat infiltration: studies in a pig model of childhood malnutrition, Am J Transl Res 2013, 5:543-554
[3] Debnath A, Bhattacharjee N: Factors Associated with Malnutrition among Tribal Children in India: A Non-Parametric Approach, J Trop Pediatr 2014, Ahead of Print.
[4] Miyazaki T, Matsuzaki Y: Taurine and liver diseases: a focus on the heterogeneous protective properties of taurine, Amino Acids 2012, 46:101-110
[5] Merino-Sanjuan M, Catalan-Latorre A, Nacher A, Miralles-Arnau S, Jimenez-Torres NV: Animal model of undernutrition for the evaluation of drug pharmacokinetics, Nutr Hosp 2011, 26:1296-1304
Reference: PAGE 23 (2014) Abstr 3089 [www.page-meeting.org/?abstract=3089]
Poster: Drug/Disease modeling - Other topics