Target-Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat.
To understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). We performed a microdialysis study in rats to obtain detailed plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-glycoprotein (P-gp) functioning on brain distribution, we performed experiments in the absence or presence of the P-gp inhibitor tariquidar (TQD). PK and PKPD modeling was performed by nonlinear mixed-effect modeling. Plasma, brain ECF, and CSF PK values of RIS and PAL were well described by a 12-compartmental semi-PBPK model, including metabolic conversion of RIS to PAL. P-gp efflux functionality was identified on brain ECF for RIS and PAL and on CSF only for PAL. In the PKPD analysis, the plasma drug concentrations were more relevant than brain ECF or CSF concentrations to explain the prolactin response; the estimated EC50was in accordance with reports in the literature for both RIS and PAL. We conclude that for RIS and PAL, the plasma concentrations better explain the prolactin response than do brain ECF or CSF concentrations. This research shows that PKPD modeling is of high value to delineate the target site of drugs.
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands shimizu.shinji.d3@daiichisankyo.co.jp ecmdelange@lacdr.leidenuniv.nl.
Shinji
S
Shimizu
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
Sandra M
SM
den Hoedt
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
Victor
V
Mangas-Sanjuan
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
Sinziana
S
Cristea
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
Jana K
JK
Geuer
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
Dirk-Jan
DJ
van den Berg
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
Robin
R
Hartman
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
Francisco
F
Bellanti
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands shimizu.shinji.d3@daiichisankyo.co.jp ecmdelange@lacdr.leidenuniv.nl.
Elizabeth C M
EC
de Lange
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002555:Cerebrospinal Fluid / Q000737:chemistry; D045604:Extracellular Fluid / Q000737:chemistry; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D000068882:Paliperidone Palmitate / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D011388:Prolactin / Q000097:blood*; D017208:Rats, Wistar; D018967:Risperidone / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011388:Prolactin; D018967:Risperidone; D000068882:Paliperidone Palmitate