Influence of P-glycoprotein (P-gp) induction on the pharmacokinetics of risperidone and paliperidone in mouse brain

P-glycoprotein (P-gp) is responsible for active efflux of drugs at the blood-brain barrier (BBB). With this study we wanted to investigate the consequences of P-gp induction on the pharmacokinetics of the known P-gp substrates risperidone and its active metabolite 9-OH-risperidone (paliperidone) in P-gp wildtype (WT) mice (FVB/N) and double-knockout (KO) mice (mdr1a/1b -/-/-/-). We used the known P-gp inducing substances dexamethasone (50mg/kg/d) and 5-pregnene-3beta-ol-20-one-16alpha-carbonitrile (PCN) (25mg/kg/d) for our study and injected them i.p. for 4 days. As controls solvent only was injected. On day 5 risperidone (3mg/kg) was i.p. injected. 1, 3 and 6h after the risperidone injection brain levels of risperidone and paliperidone were analysed using a reversed phase high performance liquid chromatography (RP-HPLC) method. The active moiety, sum of risperidone and paliperidone, were calculated due to their similar receptor profile and pharmacological effect with respect to therapeutic drug monitoring (TDM) standards. The results demonstrate the outstanding influence of transporter proteins in the disposition of risperidone and paliperidone. Brain levels of the active moiety were significantly changed in both induction groups. Both inducers showed distinct decreases in the area-under-the-data (AUD) and the brain versus plasma (B/P) ratios. But the results of the KO mice and the risperidone vs. 9-OH-risperidone (RIS:9-OH-RIS) ratios suggest that other mechanisms must be involved.