Oxidative drug metabolism and inducibility by phenobarbital in sickle cell anemia

The plasma elimination rates of antipyrine and phenylbutazone were studied in 8 patients with sickle cell anemia. The mean antipyrine half-life (t 1 2) in plasma was not significantly different in the sickle cell patients (12.0 ± 3.0 hr) than in a control group of 20 normal subjects (12.7 ± 0.9 hr). For phenylbutazone the mean t 1 2 was shorter in the sickle cell patients (2.1 ± 0.1 days) than in normal subjects (3.3 ± 0.2 days, p < 0.001); both mean apparent volume of distribution (aVD) and mean metabolic clearance rate (MCR) for this drug were significantly higher in the sickle cell group, which suggests increased extravascular distribution as well as more rapid hepatic metabolism. After administration of phenobarbital (2 to 3 mg/kg daily for 2 wk) consistent increases in rates of antipyrine and phenylbutazone metabolism were observed in 6 sickle cell anemia patients, which wr0e comparable to those observed in 5 normal subjects. Two other patients who were taking drugs (methyltestosterone, isoniazid) known to alter cytochrome P-450 function did not respond typically. Our results suggest that cytochrome P-450 function and sensitivity to phenobarbital induction are unimpaired in most sickle cell anemia patients. Since uptake of heme into hepatocytes is probably increased in this disorder, this suggests that an adapative response develops during long-term hemolysis such that heme biosynthesis and formation of microsomal cytochromes are not repressed.