A Minimal Compartmental Model for the Assessment of Net Whole Body Protein Breakdown, Using a Pulse of Phenylalanine and Tyrosine Stable Isotopes in Humans
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RationaleWe recently developed a novel and easytouse approach to measure net whole body protein breakdown (netPB), using noncompartmental modelling after single pulse injection of the stable isotopes phenylalanine (PHE) and tyrosine (TYR). We further finetuned this approach by developing a minimal compartmental model to add structural information to amino acids kinetics in PB with high precision.MethodHealthy human subjects (8 male, 6 female, age: 59.6 9.0 years) were given in the post absorptive state a single pulse (8ml) injection of L[ring13C6]PHE (6.44 mg/ml) and L[ring2H4]TYR (0.46 mg/ml). Multiple plasma samples were collected for 120 min and tracertracee ratio of PHE (mass 6) and TYR (mass 4 and 6) were measured by LCMS/MS. A four compartment model was developed to describe the kinetics of PHE and TYR and the PHE to TYR hydroxylation. The model is a priori identifiable from the PHE6 and TYR6 data measured following the PHE6 injection, provided that the TYR6 accessible pool size is known. Since this pool represents plasma and rapidly equilibrating tissues (mainly the liver) where the PHE to TYR interconversion takes place, its pool size was assumed to be equal to 25% of the whole body TYR pool size, estimated from the TYR4 decay curve. The model, identified by using SAAM, was able to reproduce the experimental data of all individuals, and all its parameters were estimated with high precision (VC%: 14.78 7.77). Our model provides estimates of compartmental fluxes, including the plasma appearance of PHE and TYR, and the PHE to TYR interconversion. These fluxes were compared to their counterparts, estimated via noncompartmental analysis in order to assess the physiological relevance of the estimated variables.ResultsThe following data were obtained by noncompartmental versus compartmental analysis for NetPB (6.998 2.237 umol/FFM kg/h, versus 6.475 1.899 umol/FFM kg/h, resp.), rate of appearance of PHE (53.626 7.479 umol/FFM kg/h versus 49.675 5.137 umol/FFM kg/h, resp.), rate of appearance of TYR in plasma (44.686 9.012 umol/FFM kg/h versus 45.879 9.110 umol/FFM kg/h, resp.). These data suggest that our model is physiologically meaningful.ConclusionOur data reveal that after single pulse injection of PHE and TYR stable isotopes, a minimal compartmental model analysis estimates net PB with low variability when the physiology of PHE to TYR conversion is included in the model estimations. Furthermore, our model may provide more detailed insight in the metabolism of these amino acids.
