Aminolevulinic acid-44 l4C1 and ['HI-bilirubin were administered intravenously to five patients with Gilbert's syndrome and four healthy control subjects on two occasions: before and on days 10 through 14 of a course of phenobarbital (2.5 mg/kg/day). The resulting curves of [SH]-bilirubin and ['4Cl-bilirubin in plasma were analyzed by computer to determine a number of parameters of physiological interest. As expected, phenobarbital produced a highly significant fall in the plasma concentration of unconjugated bilirubin as a result of a significant increase in hepatic bilirubin clearance in all subjects; plasma bilirubin turnover was unaltered. Surprisingly, the drug produced no change in the incorporation of ['"CI-6aminolevulinic acid into [14C]-early labeled bilirubin.
To explain this unexpected finding, the effects of phenobarbital (75 mg/kg/day for 6 days) on incorporation of C14Cl-I-aminolevulinic acid and 2-tl4C1glycine into [14C]-early labeled bilirubin and on the activity of the enzyme I-aminolevulinic acid synthase were studied in nonfasted, adult, male Sprague-Dawley rats. At the dose and duration of treatment used, phenobarbital administration increased total hepatic I-amholevulinic acid synthase activity and produced a significant increase of 70% in the incorporation of [*%I-glycine into early labeled bilirubin. By contrast, no increase in the incorporation of [l4CI-Iaminolevulinic acid into early labeled bilirubin was observed. These data suggest that 6-aminolevulinic