IMPORTANCE OF TISSUE AND PLASMA BINDING IN DETERMINING THE RETENTION OF NORCHLORCYCLIZINE AND NORCYCLIZINE IN MAN, DOG AND RAT

¹ The Wellcome Research Laboratories, Burroughs Wellcome & Co. (U.S.A.), inc., Tuckahoe, New York

Norcyclizine is eliminated by the rat, dog and human much more rapidly than is the structurally similar compound, norchlorcyclizine. The finding that norchiorcyclizine is more extensively bound to tissue and plasma protein than is norcycizine offers a possible explanation for the slow elimination of norchiorcycizine. Extrapolation of the data obtained by equilibrium dialysis indicates that an undiluted lung homogenate binds 98% of the added norchlorcyclizine but binds only 91.7% of the added norcyclizine. Thus, the free concentration of norcyclizine is about 4 times that of norchlorcycizine. Similarly, norchlorcyclizine is bound to kidney, liver, brain and heart more extensively than is norcyclizine. The binding to tissue of both compounds, however, is greater than the binding to plasma. Undiluted plasma binds only 88% of the added norchlorcyclizine and 59% of the added norcyclizine. Because of this extensive binding to tissue only small amounts of the administered drug are found in the plasma. The studies on the disappearance of norchlorcychzine and norcyclizine from human plasma therefore necessitated the use of an extremely sensitive method for the assay of secondary amines. After termination of chlorcyclizine treatment (50 t.i.d. for 6 days), norchiorcyclizine disappeared slowly from plasma with a half-life of 6 days, whereas the levels of norcycizine found after similar cyclizine administration were lower and disappeared from the plasma much more rapidly. The long persistence of norchlorcyclizine in the tissues following chlorcycizine administration can be seen in experiments which show that tissue levels as high as 120 µg/g of norchlorcyclizine are still found 10 days after the termination of chlorcyclizine administration to dogs.