Alteration of drug pharmacodynamics by hyperlipidemia.
Circulating lipid levels, when elevated, can alter the pharmacodynamics of lipophilic drugs presumably by acting as an additional storage depot for such drugs. Prostaglandin E1 (PGE1) and phenylephrine produced less effect on the blood pressure of atherosclerotic-hyperlipidemic rabbits than of control rabbits. This difference was apparently not due to alterations in vascular smooth muscle since aortic strips from the normal and severely atherosclerotic rabbit responded identically to the contractile effects of these drugs. Further, hyperlipidemic rats which had not yet become atherosclerotic were less responsive to the convulsant effects of fluorthyl, a highly lipophilic drug. In the presence of emulsified fat the contractile response of the rat ileum in vitro to PGE1 and acetylcholine was greatly reduced. The inhibition was reversed when fat was removed from the bathing solution. The response to PGE1, which is more lipid-soluble than acetylcholine, was more sensitive to inhibition by the presence of lipid. Finally, the pharmacokinetics of intravenously administered sulfamerazine, a lipophilic drug, appeared to be altered in the hyperlipidemic rabbit.