To characterize the transport system of
cimetidine, an organic
cation, in the blood-cerebrospinal fluid barrier, the accumulation of
cimetidine by the isolated rat choroid plexus was examined. Accumulation of
cimetidine was against a concentration gradient via a saturable process (Km = 53 microM, Vmax = 12 nmol/ml/min) that was inhibited by
sulfhydryl reagents (
p-hydroxymercuribenzoate), metabolic inhibitors (KCN and
2,4-dinitrophenol) and
hypothermia (Q10 = 4.5), but did not require inward Na+ gradient. Organic
cations such as 1N-methylnicotinamide,
tetraethylammonium,
choline,
histamine and
creatinine did not affect the accumulation of
cimetidine at the concentration of 1 mM.
Cimetidine did not affect the accumulation of
tetraethylammonium. More lipophilic
cations such as
quinidine and
quinine inhibited not only the accumulation of
cimetidine but also that of an organic
anion,
benzylpenicillin, although the inhibitory mechanisms are not known. One millimolar of organic
anions, such as 5-hydroxyindoleacetic
acid,
p-aminohippuric acid,
homovanillic acid,
salicylic acid and
benzylpenicillin, inhibited the accumulation of
cimetidine. Furthermore, the accumulation of organic
anions (
benzylpenicillin and
salicylic acid) showed saturability and was inhibited by
cimetidine.
Cimetidine and the organic
anions thus showed a mutual inhibition.
Oligopeptides also inhibited the accumulation of
cimetidine. These findings suggested that
cimetidine transport in the choroid plexus is via carrier-mediated active transport process, but does not require inward Na+ gradient. This transport is inhibited by several compounds with different properties like
oligopeptides, lipophilic
cations and organic
anions, although the inhibitory mechanism is not known.