The effects of plasma proteins on delayed repolarization in vitro with cisapride, risperidone, and D, L-sotalol.
BACKGROUND
Drug-induced long QT syndrome (LQTS) has been linked to arrhythmias (including Torsades de Pointes and sudden cardiac death), and has led to an increased awareness of the potential risk of delayed repolarization in vitro and in vivo. However, in vitro assessments of delayed repolarization have not been fully predictive of in vivo effects.


METHODS
To define the extent to which plasma protein binding (ppb) contributes to such disparities in repolarization studies, we compared drug-induced prolongation of the canine Purkinje fiber action potential duration (APD(90)) in vitro during superfusion with 100% Tyrode's solution (Tyrodes), canine plasma [50% plasma/50% Tyrodes] and a 5% solution of recombinant human serum albumin in Tyrodes (HSA). Drugs evaluated included cisapride (>98% ppb), risperidone (90% ppb), and d, l-sotalol (negligible ppb). Effects on APD were monitored using standard microelectrode techniques under physiologic conditions and temperature ([K(+)]=4 mM, 37 degrees C) during slow stimulation (2 s basic cycle length).


RESULTS
The effects of cisapride and risperidone on Purkinje fiber APD(90) were significantly attenuated in the presence of plasma proteins. However, with cisapride, the extent of reduction with plasma proteins was significantly less than predicted based on calculated free drug levels.


CONCLUSIONS
We conclude that while plasma protein binding does reduce APD prolongation seen with bound drugs, this effect is not well correlated with the calculated plasma protein binding or expected clinical free fraction. Because of the complex drug interactions that occur in plasma, the electrophysiological effects seen with bound drugs are not well correlated with the calculated free fraction and thus caution should be exercised when assigning a predictive safety window. Thus, the canine Purkinje fiber assay is useful for defining the modulation of delayed repolarization due to plasma protein binding of novel therapeutic agents.
Limberis
James T
JT
Department of Integrative Pharmacology, Abbott, Abbott Park, Illinois 60064-6119, USA. james.limberis@abbott.com <james.limberis@abbott.com>
McDermott
Jeff S
JS
Salmen
Heinz J
HJ
Su
Zhi
Z
Mikhail
Ann
A
Green
Jonathon R
JR
Cox
Bryan F
BF
Gintant
Gary A
GA
Martin
Ruth L
RL
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D020117:Cisapride / Q000009:adverse effects / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007552:Isotonic Solutions; D008954:Models, Biological; D011485:Protein Binding; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D018967:Risperidone / Q000009:adverse effects / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism / Q000494:pharmacology; D013015:Sotalol / Q000009:adverse effects / Q000378:metabolism*
D001798:Blood Proteins; D007552:Isotonic Solutions; D012709:Serum Albumin; C037692:Tyrode's solution; D013015:Sotalol; D018967:Risperidone; D020117:Cisapride