PHARMACOKINETIC EVALUATION OF THE INVITRO AND INVIVO PHARMACOLOGICAL PROFILE OF THE MAJOR METABOLITES OF KETANSERIN IN THE RAT

  • 1 June 1988
    • journal article
    • research article
    • Vol. 38-1  (6) , 785-788
Abstract
In order to explain the differences between the in vitro andpharmacological actiivty of two major metabolites of ketanserin ((+)-3-[2-[4-(4-fluorobenzyl)-1-piperidinyl]-2,4(1H,3H)-quinazolinedione, R 41 468), viz. 6-hydroxyketanserin and ketanserin-ol, the pharmacokinetics of ketanserin and both metabolites were studied after oral and subcutaneous administration to male Wistar rats. The intrinsic potency of 6-hydroxyketanserin as a serotonin S2-antagonist is similar to that of ketanserin, as assessed by receptor-binding and pharmacological studies in vitro. In vivo, both substances are equipotent after s.c. administration, but 6-hydroxyketanserin is shorter acting and has a weak oral activity. In vitro studies indicated that ketanserin-ol is 2-3 orders of magnitude less potent than ketanserin and 6-hydroxyketanserin, but its in vivo activity is higher than could be expected from the in vitro studies. When ketanserin was administered to rats, only ketanserin and none of the metaboites was detected in plasma, indicating that the parent drug is the pharmacologically active substance. After s.c.administration of 6-hydroxyketanserin, its plasma levels decreased rapidly, explaining its short duration of action. The oral bioavailability of 6-hydroxyketanserin was very low, accounting for its low in vivo activity after oral administration. The rapid elimination and the low bioavailability of 6-hydroxyketanserin are explained by hepatic conjugation and subsequent biliary excretion. After administration of ketanserin-ol to rats, the metabolite was converted in vivo to ketanserin giving much higher plasma levels for ketanserin than for ketanserin-ol. This elucidates the discrepancy between the in vitro and in vivo pharmacological activity of ketanserin-ol, which may have an indirect role in prolonging the activity of ketanserin particularly in man. In conclusion, the pharmacological activity of ketanserin in rats is due to the parent drug and none of its metabolites has a direct substantial contribution to the overall effect of the drug. The same conclusion is thought to be valid for man, too.