Lipophilic drugs and lipoproteins: partitioning effects on chloroethylnitrosourea reaction rates in serum

RJ Weinkam, A Finn, VA Levin and JP Kane

Chloroethylnitrosoureas are anticancer agents that undergo chemical reactions in vitro and in vivo to form active alkylating agents. The rate at which lipophilic chloroethylnitrosourease decompose in serum is faster than in aqueous solution and comparable to in vivo clearance rates. The increase in reaction rate is known to be caused by a reaction catalyzed by protein. Addition of lipoproteins to serum stabilizes chloroethylnitrosoureas to degradation. A model is presented that correlates serum decomposition rates to lipoprotein concentrations. This model involves partitioning of lipophilic chloroethylnitrosoureas into the hydrophobic core region of the lipoproteins where the chloroethylnitrosourea is chemically stable and is not free to undergo protein binding nor aqueous chemical degradation reactions. Normal interindividual variations of serum lipoprotein concentrations and hence partitioning may be a significant factor affecting the tissue distribution and pharmacokinetics of lipophilic drugs.

Volume 214, Issue 2, pp. 318-323, 08/01/1980
Copyright © 1980 by American Society for Pharmacology and Experimental Therapeutics