SINGLE DOSE AND STEADY-STATE PHARMACOKINETICS OF ORAL CREATINE

Abstract

Supplementation with exogenous creatine (Cr) has shown physiological benefits in athletes; animal-based disease models of Huntington's, Parkinson's, and Duchenn's Muscular Dystrophy; and clinically in patients with Gyrate Atrophy, various other neuromuscular disorders, and Congestive Heart Failure. Although the ‘pharmacological' outcome measures of Cr have been investigated, the behavior of Cr in the blood is still not fully understood. PURPOSE: To understand the effects of repeated Cr administration on the time course of Cr absorption, distribution, and elimination in blood in humans. METHODS: Six healthy males (mean ± SD, age 27.3 ± 2.8 yr, body mass 82.3 ± 16.3 kg) completed an open-label, non-controlled study consisting of 2 d of 8 h of blood collection following a single oral dose of Cr (0.071 g kg−1 ∼5 g for 70 kg man) separated by 6 d of a Cr loading period (4 × 0.071 g kg−1). Diet was controlled on days of pharmacokinetic analysis. Blood samples were also collected each morning of the loading phase before the first dose of the day, and all blood samples were analyzed by HPLC for Cr. Plasma concentration-time profiles were analyzed by non-compartmental analysis. Specifically, the following parameters were calculated for each subject: clearance (CL), area under the curve (AUC), volume of distribution (Vss/F), half-life (t1/2), and accumulation (R). RESULTS: Body weight pre- and post-supplementation increased 0.8 kg (p < 0.01). Prior to supplementation, baseline plasma Cr was 10.8 ± 3.1 mg L−1. A single oral dose was found to have a CL = 16.2 L h−1, Vss/F = 55.4 L, AUC(0–8 h) = 353.4 mg h L−1 and a t1/2 = 2.0 h. During the 6 d loading phase, resting steady-state blood levels (95.5 ± 14.5 mg L−1) were obtained between Days 3–4. At steady-state, CL decreased to 7.0 L h−1 (p < 0.05), Vss/F decreased to 37.5 L (p < 0.01), AUC(0–8 h) increased to 657.6 mg h L−1 (p < 0.001), t1/2 increased to 3.3 h (p < 0.05), and R was estimated at 60.4%. CONCLUSION: Repeated dosing of Cr causes a reduction in clearance and volume of distribution most likely caused by saturation of the skeletal muscle pool of Cr. Based on these findings, in conjunction with urinary data from the literature, both skeletal muscle and the kidney are important in eliminating Cr during early doses but later doses (after 3 d) the kidney may exclusively eliminate Cr. This information can be used to optimize Cr dosing in healthy and patient populations. Supported by ACSM Foundation/EAS Research Grant on Sports Nutrition and Human Performance.