The purpose of this investigation was to determine the effect of phenobarbital on the systemic availability of orally administered dicumarol in rats. Adult male Sprague‐Dawley rats, matched for dicumarol free fraction in serum, received either phenobarbital sodium, 75 mg/kg, or saline solution, orally or intravenously, daily for 7 days. On Day 6, they also received 14C‐dicumarol, 2 mg/kg iv, and unlabeled dicumarol, 50 mg/kg po, in aqueous suspension. Venous blood samples were obtained serially over 32 hr through an indwelling cannula. Systemic dicumarol availability was determined from the dose‐normalized ratio of areas under the plasma concentration‐time curves. Phenobarbital treatment almost doubled the total clearance of dicumarol and the intrinsic clearance of free dicumarol, with no significant difference between the inductive effects of oral and intravenous doses of phenobarbital. Systemic dicumarol availability in control rats (mean ± SD) was 84 ± 8% (n = 10) and 84 ± 10% (n = 6) in the oral and intravenous phenobarbital studies, respectively. The systemic dicumarol availability in phenobarbital‐treated rats was appreciably lower: 48 ± 7% (n = 10) and 61 ± 12% (n = 6) for orally and intravenously treated animals, respectively. The effect of oral phenobarbital on systemic dicumarol availability was more pronounced than that of intravenous phenobarbital (p < 0.025). The apparent first‐order absorption rate constants for the fraction of the dose available systemically were similar for control and treated animals. There was a positive correlation between systemic dicumarol availability and total dicumarol clearance in control animals (p < 0.001). Proper matching of control and treated animals is, therefore, important for this type of study. The rat appears to be a good model for investigating the mechanism of the inhibitory effect of phenobarbital on dicumarol absorption observed previously in humans. Copyright © 1979 Wiley‐Liss, Inc., A Wiley Company
