Morphine, 20 mg X kg-1, sc, halved the plasma clearance of sulfobromophthalein (BSP) while tripling hepatic tissue levels of this dye. Since narcotics depress respiration, effects of hypoxia, hypercapnia, and acidosis on BSP disposition were studied. Ambient gases breathed by rats were adjusted to achieve blood gas levels identical to those of morphine-induced respiratory depression. Saline-treated rats breathing room air had PAO2 of 87 +/- 3 mmHg (mean +/- SE) and PaCO2 of 40 +/- 2 mmHg. After intraarterial injection of BSP, 100 mg X kg-1, plasma clearance of this dye was 7.1 +/- 1.1 ml X min-1 and BSP levels in the liver at 40 min after injection were 163.3 +/- 19.8 micrograms X g-1. After morphine, 20 mg X kg-1, PaO2 decreased to 47 +/- 4 mmHg and PaCO2 increased to 89 +/- 5 mmHg. In these rats BSP clearance dropped to 3.5 +/- 0.4 ml X min-1, and 40-min liver dye levels were increased to 596.4 +/- 60.4 micrograms X g-1. Similar hypoxia and hypercapnia caused by breathing 9% O2 and 8% CO2 in the absence of morphine caused plasma BSP clearance to be decreased to 4.4 +/- 0.2 ml X min-1 and 40-min hepatic BSP to be increased to 292.5 +/- 31.8 micrograms X g-1. Hypercapnia and acidosis alone did not affect BSP disposition, while hypoxia without hypercapnia decreased its plasma clearance to 5.5 +/- 0.3 ml X min-1 and increased liver levels to 339.1 +/- 35.1 micrograms X g-1. Hypoxia was reversed completely in morphine-treated rats by placing them in 40% O2. In these animals, despite normal oxygen, plasma BSP clearance was decreased to 4.4 +/- 0.6 ml X min-1, and liver BSP was increased to 497.9 +/- 65.6 micrograms X g-1. Thus, respiratory depression with hypoxia may contribute to morphine-induced effects on BSP disposition, but altered blood gases cannot account fully for these narcotic effects.