The impact of paroxetine coadministration on stereospecific carvedilol pharmacokinetics.
OBJECTIVE
to assess the impact of paroxetine coadministration on the stereoselective pharmacokinetic (PK) properties of carvedilol.


METHODS
prospective, randomized, 2-phase crossover.


METHODS
the University of Michigan General Clinical Research Unit and Michigan Clinical Research Unit.


METHODS
twelve healthy volunteers aged 18 to 45 years, male and female, receiving no treatment with prescription or nonprescription medications.


METHODS
participants received single dose oral carvedilol (12.5 mg) with and without coadministration of immediate-release paroxetine (10 mg orally twice daily), in random order. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 hours post-carvedilol dose for determination of R and S carvedilol plasma enantiomer concentrations by high pressure liquid chromatography.


RESULTS
pharmacokinetic (PK) parameters were calculated for each enantiomer by noncompartmental methods and compared between study phases by analysis of variance (ANOVA) controlling for study phase order and subject, with Tukey's studentized range test post hoc. Area under the concentration-time curve (AUC) increased significantly with paroxetine coadministration, approximately 2.5-fold and 1.9-fold for the R and S enantiomers, respectively. R/S AUC ratio increased significantly, from approximately 2.3 to 3.0. Individual increases in enantiomeric AUCs with paroxetine coadministration ranged from 0% to 571% and changes in R/S ratio ranged from -8% to 108%. Heart rate, P-R interval, and blood pressure were monitored and no clinically significant changes in carvedilol effects were noted.


CONCLUSIONS
this study demonstrated a PK drug-drug interaction between paroxetine and carvedilol, with considerable interparticipant variability in carvedilol PK parameters and magnitude of drug interaction. Stereoselectivity of carvedilol metabolism is preserved with paroxetine coadministration, and R/S AUC ratio generally widens. Although this drug interaction could potentially increase adrenergic antagonism and have significant clinical effects in patients, these effects were not seen in our healthy volunteer participants.
Stout
Stephen M
SM
The University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA.
Nielsen
Jace
J
Bleske
Barry E
BE
Shea
Michael
M
Brook
Robert
R
Kerber
Kevin
K
Welage
Lynda S
LS
D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects*; D002227:Carbazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077261:Carvedilol; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000008:administration & dosage / Q000494:pharmacology*; D011412:Propanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013237:Stereoisomerism
D000959:Antihypertensive Agents; D002227:Carbazoles; D000077261:Carvedilol; D017374:Paroxetine; D011412:Propanolamines; D017367:Selective Serotonin Reuptake Inhibitors