Stereoselective differences in propranolol disposition in female Sprague-Dawley and Dark Agouti rats.
Although genetic constitution is recognized as an important factor in drug elimination, there is still only a modest amount of information about its impact on stereoselective drug disposition. To examine how strain differences in cytochrome P-450 expression may affect stereoselective drug elimination, the disposition of R- and S-propranolol was examined in female Sprague-Dawley (SD) and Dark Agouti (DA) rats. The half-life of R-propranolol was increased and its apparent oral clearance decreased significantly in DA rats relative to the SD strain [85 +/- 41 min (DA) vs. 26 +/- 10 min (SD) and 0.020 +/- 0.014 liter/min/kg (DA) vs. 0.31 +/- 0.14 liter/min/kg (SD)], respectively. Strain differences in S-propranolol half-life and apparent oral clearance also were observed, but were not as marked [97 +/- 36 min (DA) vs. 52 +/- 35 min (SD) and 0.20 +/- 0.13 liter/min/kg (DA) vs. 0.70 +/- 0.68 liter/min/kg (SD)], respectively. Due to a more pronounced effect of rat strain on the disposition of R-propranolol, the stereoselective S-/R- oral clearance ratio for propranolol was also strain-dependent [10 +/- 3 (DA) vs. 2.1 +/- 0.9 (SD)]. These differences could not be accounted for by propranolol stereoselective plasma protein binding or by a difference in the blood/plasma ratio for R- or S-propranolol in these separate strains. This represents one of the few examples where an increase in stereoselective drug disposition has been observed due to strain differences that diminish drug elimination.
Guttendorf
R J
RJ
College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Kostenbauder
H B
HB
Wedlund
P J
PJ
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D006207:Half-Life; D010641:Phenotype; D011433:Propranolol / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014018:Tissue Distribution
D001798:Blood Proteins; D011433:Propranolol; D003647:Debrisoquin