Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria

Aims Large oral doses of betaine have proved effective in lowering plasma homocysteine in severe hyperhomocysteinaemia. The pharmacokinetic characteristics and metabolism of betaine in humans have not been assessed and drug monitoring for betaine therapy is not available. We studied the pharmacokinetics of betaine and its metabolite dimethylglycine (DMG) in healthy subjects and in three patients with homocystinuria. Methods Twelve male volunteers underwent an open-label study. After one single administration of 50 mg betaine kg(-1) body weight and during continuous intake of twice daily 50 mg kg(-1) body weight, serial blood samples and 24 h urines were collected to determine betaine and DMG plasma concentrations and urinary excretion, respectively. Patients were evaluated after one single dose of betaine. Results We found rapid absorption (t(1/2,abs) 00.28 h, s.d. 0.17) and distribution (t(1/2, lambda1) 00.59 h, s.d. 0.22) of betaine. A C-max of 0.94 mmol l(-1) (s.d. 0.19) was reached after t(max) 00.90 h (s.d. 0.33). The elimination half life t(1/2,z) was 14.38 h (s.d. 7.17). After repeated dosage, t(1/2,lambda1) (01.77 h, s.d. 0.75) and t(1/2,z) (41.17 h, s.d. 13.50) increased significantly (95% CI 0.73, 01.64 h and 19.90, 33.70 h, respectively), whereas absorption remained unchanged. DMG concentrations increased significantly after betaine administration and accumulation occurred to the same extent as with betaine. Renal clearance was low and urinary excretion of betaine was equivalent to 4% of the ingested dose. Distribution and elimination kinetics in homocystinuric patients appeared to be accelerated. Conclusions Betaine plasma concentrations change rapidly after ingestion. Elimination half-life increased during continuous dosing over 5 days. Betaine is mainly eliminated by metabolism. More pharmacokinetic and pharmacodynamic studies in hyperhomocysteinaemic patients are needed to refine the current treatment with betaine.