Hepatic microsomal drug metabolism in the pregnant rat.

1. Hepatic microsomal drug metabolism determined with the substrates aniline (p-hydroxylation), ethylmorphine (N-demethylation) and p-nitrobenzoic acid (reduction), decreased during gestation in the rat to 53-73% of non-pregnant control levels by day 20 of gestation. 2. Enzyme activity remained low at one day post-partum, but had returned to control non-pregnant levels by five days post-partum. 3. The total capacity of the liver to metabolize drugs remained unchanged or increased because liver weight was increased by up to 40% during pregnancy. 4. Changes in drug metabolism were not related to alterations in the concentration, substrate-induced binding affinity (Ks) or maximal spectral change (delta Amax) of cytochrome P-450. 5. Alterations in hepatic drug metabolism are possibly mediated via changes in microsomal phospholipids and/or the cytochrome P-450 spin-state equilibrium as as pregnancy was associated with a decrease in (a) microsomal total phospholipids, (b) the phosphatidylcholine to phosphatidylethanolamine ratio and (c) the high-spin form of ferricytochrome P-450.