UPTAKE OF CIMETIDINE INTO SYNCYTIAL MICROVILLUS MEMBRANE-VESICLES OF HUMAN TERM PLACENTA

Uptake of the H-2-receptor antagonist, cimetidine, into syncytial micr ovillus membrane vesicles of human term placenta was investigated to c larify whether an active transport mechanism can be responsible for th e observed barrier of the human placenta for cimetidine, Imposition of an outwardly directed H+-gradient stimulated cimetidine uptake, resul ting in a small transient overshoot, The H+-gradient-dependent peak up take was decreased under voltage-clamped conditions by carbonyl cyanid e p-trifluoromethoxy-phenylhydrazone, suggesting the presence of an or ganic cation-proton exchange mechanism. Uptake was partially, but sign ificantly, inhibited by organic cation transport inhibitors, H-2-recep tor antagonists and several other cationic drugs, providing further ev idence for mediated uptake. H+-gradient-dependent cimetidine uptake wa s saturable and characterized by a low-affinity (K-m) of 6.3 mM and V- max of 17.5 nmol/mg protein/10 sec. We conclude that the system cannot play an important role in the barrier function of the human placenta in the transport of cimetidine. Rather than active transport, other fa ctors, as for instance the degree of ionization of cimetidine at physi ological pH, seem to be a more likely explanation for the low clearanc e of cimetidine across the human placenta.