Population pharmacokinetic analysis of drug-drug interactions among risperidone, bupropion, and sertraline in CF1 mice.
BACKGROUND
Accumulating evidence indicates that modulation of the activity of cytochrome P450 (CYP) enzymes and the multidrug resistance transporter P-glycoprotein (P-gp) is responsible for many drug-drug interactions.


OBJECTIVE
The potential interaction of risperidone (RISP), which is metabolized by 2D6 and transported across the blood brain barrier (BBB) by P-gp, was studied in combination with bupropion (BUP) and also with sertraline (SERT).


METHODS
BUP, SERT, and RISP were administered intraperitoneally into CF1 mice at doses of 100, 10, and 1 microg/g mouse, respectively. Plasma and brain samples were collected at timed intervals from 0.5 to 6 h. A pharmacokinetic analysis was performed using both traditional compartmental modeling and a population pharmacokinetic approach.


RESULTS
BUP increased the RISP plasma (5.9-fold, P<0.01) and brain (2.2-fold, P<0.01) area under the drug concentration vs time curve (AUC), but did not alter the brain-to-plasma concentration ratio. SERT did not significantly change the plasma AUC of RISP and 9-hydroxy-RISP, but increased the brain AUC of RISP and 9-hydroxy-RISP 1.5-fold (P<0.05) and 5-fold (P<0.01), respectively. RISP did not produce significant alterations of plasma or brain concentrations of BUP. It increased the plasma AUC and elimination half-life (T1/2e) of desmethyl-SERT 12.5-fold (P<0.01) and 107-fold (P<0.01), respectively.


CONCLUSIONS
These results suggest that pharmacokinetic interactions exist among these three psychoactive drugs involving inhibition of drug metabolizing enzymes and/or P-gp and other drug transporters present in the BBB. The mechanisms and consequences of these interactions require further study in humans to establish clinical relevance.
Wang
Jun-Sheng
JS
Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, Charleston, SC 29425, USA.
DeVane
C Lindsay
CL
Gibson
B Bryan
BB
Donovan
Jennifer L
JL
Markowitz
John S
JS
Zhu
Hao-Jie
HJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D016642:Bupropion / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004347:Drug Interactions; D008297:Male; D051379:Mice; D011153:Population; D018967:Risperidone / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020280:Sertraline / Q000493:pharmacokinetics* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D012702:Serotonin Antagonists; D016642:Bupropion; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D020280:Sertraline