Cisapride (Propulsid®) October 14, 1995
A drug alert
("important safety information") was issued by Janssen Pharmaceuticals
on the above date, that "serious cardiac arrhythmias, including
ventricular tachycardia, ventricular fibrillation, torsades de pointes,
and QT prolongation have been reported in patients taking PROPULSID®
with other drugs that inhibit cytochrome P450 3A4, such as ketoconazole,
itraconazole, miconazole, troleandomycin, erythromycin, fluconazole, and
clarithromycin. Some of these events have been fatal. PROPULSID®
is contraindicated in patients taking any of these drugs." For further
information contact Janssen at Washington Crossing, 1125
Trenton-Harbourton Road, Post Office Box 200, Titusville, New Jersey
08560-0200.
Comments:
Dr. George Aronoff (Louisville, KY)
(Send
questions and suggestions to: graron01@ulkyvm.louisville.edu):
The important safety information issued by Janssen Pharmaceuticals for
cisapride is the latest in a series of alerts regarding drugs which
influence the cytochrome P-450 metabolizing system. Cytochrome P-450 is
a superfamily of more than 100 enzymes catalyzing a large number of
bioactivation and detoxication reactions. The large number of different
cytochrome enzymes and genetic polymorphism in the activity of these
enzymes complicates the use of drugs metabolized by them.
Cytochrome P-450 IIIA, one of the cytochrome enzymes, is
inhibited by
ketoconazole, itraconazole, miconazole, troleandomycin,
erythromycin, fluconazole, and clarithromycin. Drugs metabolized by
this enzyme, like cisapride, may accumulate and cause toxicity when
taken concurrently with drugs that inhibit cytochrome P-450 metabolism.
Serious arrhythmias characterized by QT prolongation, including
ventricular tachycardia, ventricular fibrillation, and torsades de
pointes have been reported. This mechanism is the same as that
previously reported for the interaction between terfenidine
(Seldane) and erythromycin.
Cyclosporine: Cytochrome P-450IIIA is also primarily
responsible for cyclosporine metabolism. Other drugs known to
inhibit cytochrome P-450IIIA include verapamil, diltiazem,
nicardipine, nifedipine, and nitrendipine, theophylline terfenadine and
astemizole.
Grapefruit juice inhibits cytochrome P-450IIIA and can enhance
the absorption of cyclosporine. Concurrent use of these drugs or the
ingestion of grapefruit juice may substantially increase cyclosporine
plasma concentrations. Although toxicity is the major concern,
ketoconazole or grapefruit juice have been used to purposely increase
cyclosporine plasma concentrations in an attempt to decrease the dose
and expense of cyclosporine.
Other cytochrome P-450 enzymes:Several other cytochrome P-450
isoenzymes have been well characterized. They include cytochrome
P-450IID6, known to metabolize the antiarrhythmic agents
encainide, flecainide, and propafenone, the beta blockers propranolol,
metoprolol, and timolol, the antidepressants fluoxetine,
paroxetine, fluoxamine, imipramine, desipramine, amitriptyline, and
nortriptyline, as well as codeine. Cytochrome P-450IIC
metabolizes the following drugs the anticonvulsants phenytoin,
mephenytoin, and methobarbital, oral hypoglycemic, tolbutamide, and
warfarin.
Because of the many drug interactions effecting
the cytochrome P-450 family of enzymes, caution should be used when
administering the many drugs metabolized by these enzymes. Establishing
specific diagnoses before drug prescribing, using as few drugs as
possible, and monitoring for efficacy and toxicity are useful in
decreasing adverse drug events.
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