Food can change drug concentrations by several mechanisms, including some that are independent of absorption effects. This study tests the hypothesis that a meal decreases zidovudine (ZDV) concentration in blood plasma independent of an effect on drug absorption. The study was conducted as a substudy nested in a larger protocol in which ZDV was given to 7 healthy men by continuous infusion for 5 days starting on day 1. The subjects received only a standardized breakfast meal on day 2 and were fasted on day 3 until the 8-hour sampling period each day was finished. Blood samples were collected through an indwelling cannula in the arm contralateral to the ZDV infusion at the same time of day on both days. It was found that food decreased the blood plasma ZDV concentration at 1 hour postprandial by 14% (5.0%-22%; geometric mean change with 95% confidence interval). This decrease recovered by 6 hours postprandial. Similar changes were seen with the ZDV primary metabolite, zidovudine glucuronide. The authors conclude that food decreases blood plasma ZDV concentrations independent of any absorption effects. This effect may be due to the increased hepatic metabolism because feeding increases hepatic blood flow and because ZDV has a high hepatic extraction ratio with low affinity to blood plasma proteins.