Effect of Clofibrate on the Chiral Disposition of Ibuprofen in Rats1

Abstract

A potentially clinically important interaction has been described between clofibrate and ibuprofen in vitro. To determine whether this in vitro interaction is paralleled by a change in pharmacokinetics of ibuprofen in vivo two groups of rats were treated orally with clofibrate (n = 8, 280 mg/kg/day) or vehicle (n = 7) for 3 days. On day 3, 2 hr after the last dose of clofibrate, the rats were given an i.v. dose of pseudoracemic ibuprofen (20 mg/kg, 10 mg R-ibuprofen, 10 mg¹³C-S-ibuprofen). Plasma concentrations of the enantiomers were monitored by a stereospecific gas chromatography mass spectrometry assay. The clearance of R-ibuprofen more than doubled in the clofibrate-treated group (mean ± S.E.M.; 29.4 ± 4.0 ml/min) as compared to control rats (13.0 ± 1.4 ml/min; P = .003). This increase was similarly reflected in the clearance by inversion (treated, 23.2 ± 3.2 ml/min, untreated, 10.0 ± 1.2 ml/min; P = .003) and there was also an increase in the rate of inversion (treated, t_1/2 inversion, 8.3 ± 1.6 min; untreated, 13.9 ± 1.4 min; P = .029). By contrast, the estimates of fractional chiral inversion were not affected by clofibrate and were in close agreement whether estimated by the area under the plasma concentration-time curve approach (treated, 0.79 ± 0.02; untreated, 0.72 ± 0.02) or by deconvolution (treated, 0.78 ± 0.02; untreated, 0.73 ± 0.02). There was a significant increase in volume of distribution at steady-state (treated, 4.42 ± 1.12 liter/kg; untreated, 1.03 ± 0.30 liter/kg; P = .017) observed for the R-enantiomer but not the S-enantiomer (treated, 1.04 ± 0.13 liter/kg; untreated, 1.10 ± 0.21 liter/kg). Pretreatment of rats with clofibrate significantly increased the concentrations of ibuprofen in fat, lung, brain and liver tissue. With respect to the protein levels of two key enzymes involved in chiral inversion, clofibrate pretreatment significantly induced expression of long chain acyl-coenzyme A synthetase, although the expression of the epimerase was unaltered. It is concluded, that clofibrate may increase the proportion of R-ibuprofen incorporated into long-lived lipid (“hybrid” lipid) stores.