Supplementation with exogenous creatine (Cr) has shown physiological benefits in humans, but little is known about the pharmacokinetics of Cr in humans. Six healthy males completed an open-label study consisting of a full pharmacokinetic analysis following a single oral dose of Cr monohydrate (71 mg kg-1) and at steady-state after 6 days of Cr administration (71 mg kg-1 qid). After the single oral dose, the clearance (CL/F) was 0.20 +/- 0.066 L h-1 kg-1, tmax was 1.9 +/- 0.88 hours, and Cmax = 102.1 +/- 11.2 mg h L-1. At steady-state, CL/F decreased to 0.12 +/- 0.016 L h-1 kg-1, tmax did not change, and Cmax increased to 162.2 +/- 30.0 mg L-1. Penetration (AUCMUSCLE/AUCPLASMA) of Cr into the interstitial muscle space, as determined by microdialysis, was 0.47 +/- 0.09 and 0.37 +/- 0.27 for the single dose and at steady-state, respectively. Plasma and muscle data were simultaneously fitted with a model incorporating a saturable absorption and first-order elimination process. In conclusion, repeated dosing of Cr caused a reduction in clearance that could result from saturation of the skeletal muscle pool of Cr.