Pharmacokinetic analysis of sparse in vivo NMR spectroscopy data using relative parameters and the population approach.

NMR spectroscopy in vivo when applied to studying drugs and their metabolites usually measures relative concentration in a tissue over time. Only ratios of clearance and volume parameters can be estimated from these data. Low drug dosages (relative to the sensitivity of in vivo NMR) or rapid drug elimination create the additional problem of data sparsity where a pharmacokinetic model cannot be fitted individually. We have investigated whether relative and absolute pharmacokinetic parameters can be estimated from such data by applying a population model. The data analysed were relative concentrations of 5-fluorouracil (FU) and of the sum of its catabolites alpha-fluoro-beta-ureido-propanoic acid (FUPA) and alpha-fluoro-beta-alanine (FBAL) in the liver, as monitored in 16 cancer patients by [19F]-NMR spectroscopy during and after a 10-min intravenous infusion of 650 mg FU.m-2. The "structural" part of the population model was a non-linear, two-compartment model featuring one FU compartment with volume VFU, a saturable clearance of FU by conversion into the catabolites where CL = vmax/(kM+CFU), a catabolite compartment with volume Vcat, and a concentration-independent clearance of the catabolites, CLcat. The parameters actually fitted were: gamma, vmax, kM.VFU, Vcat/VFU, and CLcat/Vcat where gamma is a proportionality factor relating the NMR signal intensity of FU to the amount of FU in the body and, therefore, has no purely pharmacokinetic interpretation. All parameters were checked for random interindividual variation: gamma and vmax were also tested for inter-occasion variation. The program system NONMEM was used for model fitting.(ABSTRACT TRUNCATED AT 250 WORDS)