Phenobarbital does not increase early labeling of bilirubin from 4‐[ 14 C]‐δ‐aminolevulinic acid in man and rat

δ‐Aminolevulinic acid‐4‐[ 14 C] and [ 3 H]‐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 [ 3 H]‐bilirubin and [ 14 C]‐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 [ 14 C]‐α‐aminolevulinic acid into [ 14 C]‐early labeled bilirubin. To explain this unexpected finding, the effects of phenobarbital (75 mg/kg/day for 6 days) on incorporation of [ 14 C]‐δ‐aminolevulinic acid and 2‐[ 14 C]‐glycine into [ 14 C]‐early labeled bilirubin and on the activity of the enzyme δ‐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 δ‐aminolevulinic acid synthase activity and produced a significant increase of 70% in the incorporation of [ 14 C]‐glycine into early labeled bilirubin. By contrast, no increase in the incorporation of [ 14 C]‐δ‐aminolevulinic acid into early labeled bilirubin was observed. These data suggest that δ‐aminolevulinic acid is an inappropriate precursor for studies of the rate of heme biosynthesis, presumably because it bypasses δ‐aminolevulinic acid synthase, the physiological rate‐limiting enzyme in the heme biosynthetic pathway. (H EPATOLOGY 1991;14:1153–1160.)