Pharmacokinetics of the beta-carboline norharman in man

In healthy subjects, pharmacokinetics were characterised using single oral and sublingual administrations of the beta -carboline norharman. For this p urpose, norharman levels in blood plasma were measured up to 90-105 min aft er both routes of administration. Dose proportionality of three different s ingle oral doses of norharman (7, 65 and 110 mug/kg) administered as 0.52 a nd 5 mg capsules was evaluated at 8 time points. Peak levels were attained at 30 min after the oral load of norharman. Mean relative availabilities de termined by the area under the curve (AUC) procedure were 14.3 and 98.0 nmo l.min/l after oral dosing of 7 and 65 mug/kg, respectively. AUC values in w omen were 3-4 times higher than in men. Sublingual dosing of 6.5 and 13 mug /kg norharman encapsulated in 5 mg of cyclodextrins resulted in a much high er mean AUC and a more rapid absorption. Mean AUC after sublingual administ ration of 6.5 mug/kg was 929.8 nmol.min/kg and plasma levels were maximal 1 0-15 min after norharman was given. Moreover, apparently no sex difference was found using this way of application. Norharman disappeared from the pla sma with half-lifes of 25-35 min, irrespective of the route of administrati on. Even at the highest measured norharman levels of 53 nmol/l plasma, no b ehavioral effects were observed. In addition, the subjects did neither repo rt any effects nor any side-effects during the experiment. This is the firs t study in which the kinetics of ingested norharman have been measured in h umans. (C) 2001 Elsevier Science Inc. All rights reserved.