Although metabolic response after partial hepatectomy has been well studied in animal models, there are few studies examining restoration of metabolic capacity after right hepatectomy in humans. The L-[1-(13)C]-phenylalanine breath test (PBT) is a simple non-invasive diagnostic tool which allows measurement of liver functional reserve. We investigated the PBT for monitoring hepatic function in living liver donors by measuring the metabolism of L-[1-(13)C]-phenylalanine ((13)C-Phe). We used (13)C-Phe administered orally and iv to adult living liver donor patients and measured exhaled (13)CO(2) to determine the extent of metabolic impairment and time course of its return. Patients given oral (13)C-Phe had approximately 70-90% reduction in (13)CO(2) production compared with baseline 2-3 days after surgery. Patients given iv (13)C-Phe had only 40-50% reduction in (13)CO(2) production and recovered their baseline (13)C-Phe metabolism much sooner than their oral (13)C-Phe metabolic capacity (P < 0.05). In some cases oral (13)C-Phe did not recover to baseline for as long as 56 days after surgery. Patients recovering (13)C-Phe metabolism had significantly higher (13)CO(2) recovery 60 min after ingestion by day 4 (0.97 versus 3.06, P = 0.033) and day 7 (1.50 versus 5.02, P = 0.031). We conclude that orally administered amino acids may not be well absorbed and/or metabolized in some subjects for weeks after partial hepatectomy whereas intravenously delivered substrates are much better oxidized by the regenerating liver. These findings may be due to impaired gut motility due to trauma to the gastrointestinal tract or portal venous flow that reduces delivery of oral agents after liver surgery. In early recovery phase for living liver donor patients, the iv PBT would be a better predictor of functional hepatic reserve.