Pharmacology of Risperidone – Pharmacokinetics

Absorption, bioavailability and distribution

The rate of absorption and bioavailability of drugs affects their systemic concentration hence their effect. (8). Risperidone is rapidly and completely absorbed following oral administration and has a high bioavailability.(3,4,5,7,8). Its absolute oral bioavailability is 70% (CV=25%) with the relative oral bioavailability of the tablet as compared to the solution being 94% (CV=10%). (5,7). Both the fast disintegrating and the solution risperidone are suggested to be bioequivalent to the conventional tablets. (4,7).  After oral administration, risperidone and its equally potent primary metabolite (9-hydroxy-risperidone) reach mean Cmax values at approximately 1 and 3 hours respectively i.e. their respective T max values. (3-5,8). The presence of food does not affect either the  rate (T max)  or the extent of absorption (AUC). (5,7).

For the IM administered risperidone, plasma concentration of risperidone and the principal metabolite increase gradually 3 weeks following the injection, with peak values occurring between 4 and 6 weeks subsiding by the seventh week following administration. (5,7,10-13).

Risperidone is distributed rapidly the volume of distribution (vd) being 1 to 2 L/kg. (3,4,5,7,8,13). Steady-state concentrations for risperidone are reached within 1 to 2 days while those for 9-OH-risperidone are within 5 to 6 days following administration. (3,4,8,13). The drug is highly bound by the plasma proteins; approximately 90% for risperidone and 77% for 9-OH-risperidone. (5,7,13). Risperidone and 9-OH-risperidone have approximately equal affinities for plasma binding sites, and neither of the compounds displaces the other from such sites. (5,7).

Metabolism and excretion

Drug metabolism is aimed at making the drug more water soluble to effectuate its excretion. (9). The metabolism of risperidone proceeds through hydroxylation and N-dealkylation to a pharmacologically equipotent primary metabolite, 9-OH-risperidone; a process facilitated by cytochrome P450 (CYP) complex in the liver especially by CYP2D6 and CYP3A4 . (3,4,5,7,8). The formed 9-OH-risperidone can either be a positive (+) or negative (+) enantiomer with both CYP2D6 and CYP3A4 being involved in such enantiomer-selective hydroxylation, though the formation through CYP3A4 proceeds at a slower rate. (3,5,7). 9-OH-risperidone is an equipotent metabolite of risperidone hence they both form the clinically relevant active moiety. (3,4,5,7). Drugs competing for CYP2D6 or CYP3A4 e.g. CYP2D26 inhibitors, sertraline and buproprion, alter the metabolism of risperidone to 9-OH-risperidone hence increasing its AUC and elimination half-life (t1/2). (14). The chemical structure of 9-OH-risperidone is as in the figure below with the one H being substituted by a hydroxyl group at position 9.

chemical structure

Elimination of risperidone is via renal excretion. Renal impairment thus increases AUC and t1/2 of risperidone (13) resulting from an approximate 60% decrease in clearance of the active moiety (risperidone plus 9-OH-risperidone). (5,7). In the absence of such renal impairment, the terminal half life (t1/2) of risperidone is between 1 to 2 hours in CYP2D6 intensive metabolizers but increases up to 20 hours in the case of poor metabolizers. (3,4,8). About 70% of risperidone eliminated in urine while 14% is eliminated in faeces; as evaluated through total recovery of radioactivity. (5,7,15).

Proceed to part 4 here.

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