Ticlopidine reduces metabolism of phenytoin
A 65-year-old man taking phenytoin 200mg daily and clobazam developed signs of phenytoin toxicity (vertigo,ataxia, somnolence) within a week of starting ticlopidine 250mg daily. His serum phenytoin levels had risen from 18 mg/L to 34 mg/L. When phenytoin dosage was reduced to 200mg daily toxic symptoms disappeared within a few days and his serum phenytoin levels fell to 18 mg/L. To test whether an interaction had occurred, ticlopidine was stopped, whereupon serum phenytoin levels fell, within about 3 weeks, to 8 mg/L, during which time patient
experienced his first seizure in 2 years. When ticlopidine was restarted, his serum phenytoin levels rose again, within a month, to 19 mg/L (See reference number 1). A number of other case reports describe phenytoin toxicity,which occurred within 2 to 6 weeks of starting ticlopidine 250mg once or twice daily (See reference number 2-7). These were usually managed by reducing phenytoin dose. One patient then experienced breakthrough seizures after ticlopidine was stopped without re-adjusting phenytoin dose (See reference number 6). One case in a patient also taking phenobarbital reported that no change in phenobarbital levels occurred (See reference number 4).
A study in 6 patients taking phenytoin alone found that ticlopidine 250mg twice daily approximately halved steady-state phenytoin clearance (See reference number 8)
The metabolism of phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) by cytochrome P450 isoenzyme CYP2C19, and to a lesser extent by CYP2C9, in liver is inhibited by ticlopidine (See reference number 1,3,4,9). Further metabolism of HPPH to dihydroxylated products is mediated mainly by CYP2C19 and this may also be inhibited by ticlopidine (See reference number 9).
The interaction is established and clinically important,but its incidence is unknown. It would now be prudent to monitor serum phenytoin levels very closely in any patient if ticlopidine is added to established treatment, being alert for need to reduce phenytoin dosage. If ticlopidine is discontinued, phenytoin dose may need to be increased.
Riva R,Cerullo A, Albani F, Baruzzi A. Ticlopidine impairs phenytoin clearance: a case report. Neurology (1996) 46, 1172–3.
Rindone JP,Bryan G. Phenytoin toxicity associated with ticlopidine administration. Arch Intern Med (1996) 156, 1113.
Privitera M,Welty TE. Acute phenytoin toxicity followed by seizure breakthrough from aticlopidine-phenytoin interaction. Arch Neurol (1996) 53, 1191–2.
Donahue SR,Flockhart DA, Abernethy DR, Ko J-W. Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther (1997) 62, 572–7.
López-Ariztegui N,Ochoa M, Sánchez-Migallón, Nevado C, Martín M, Intoxicación agudapor fenitoína secundaria a interacción con ticlopidina. Rev Neurol (1998) 26, 1017–18.
Klaassen SL. Ticlopidine-induced phenytoin toxicity. Ann Pharmacother (1998) 32,1295–8.
Dahm AEA,Brørs O. Fenytoinforgiftning forårsaket av interaksjon med tiklopidin. Tidsskr Nor Laegeforen (2002) 122, 278–80.
Donahue S,Flockhart DA, Abernethy DR. Ticlopidine inhibits phenytoin clearance. Clin Pharmacol Ther (1999) 66, 563–8.
Giancarlo GM,Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol (2001) 57, 31–36.