One study suggested that intravenous dipyridamole may reducethe steady-state plasma levels of fluorouracil,whereas othersfound that oral dipyridamole caused no important changes influorouracil pharmacokinetics.
Clinical evidence,mechanism, importance and management
Numerous preclinical studies found that dipyridamole enhanced activity of fluorouracil, leading to its investigation as a biomodulator (See reference number 1). However, unexpectedly, in one phase I study of combination, use of dipyridamole was associated with lower steady state plasma level of fluorouracil, suggesting an approximately 30 % increase in total body clearance or volume of distribution of fluorouracil (See reference number 2). In this study,47 patients with advanced cancer were given fluorouracil in escalating doses ranging from 185 mg/m(See reference number 2) daily to 3600 mg/m(See reference number 2) daily with or without dipyridamole as a continuous infusion of 7.7 mg/kg per day for 72 hrs (See reference number 2). In contrast, in a later randomised study, oral dipyridamole 75mg three times daily for 5 days did not significantly alter pharmacokinetics of fluorouracil, except for prolonging half-life and slightly increasing dose-intensity: over 5 cycles average dose of fluorouracil was 479 mg/m(See reference number 2) alone, compared with 533 mg/m(See reference number 2)in presence of dipyridamole. In this study, oral dipyridamole did not improve antineoplastic activity of fluorouracil and folinic acid (See reference number 3). Similarly, another clinical study found that oral dipyridamole did not significantly alter pharmacokinetics of fluorouracil (See reference number 4). Thus, despite promise of preclinical studies, benefits of combining dipyridamole with fluorouracil have not been realised clinically.
Grem JL. Biochemical modulation of fluorouracil by dipyridamole: preclinical and clinical experience. Semin Oncol (1992) 19 (Suppl 3),56–65.
Trump DL,Egorin MJ, Forrest A, Willson JKV, Remick S, Tutsch KD. Pharmacokinetic andpharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole. J Clin Oncol (1991) 9, 2027–35.
Köhne C-H,Hiddemann W, Schüller J, Weiss J, Lohrmann H-P, Schmitz-Hüber U, Bodenstein H, Schöber C, Wilke H, Grem J, Schmoll H-J. Failure of orally administered dipyridamole toenhance the antineoplastic activity of fluorouracil in combination with leucovorin in patientswith advanced colorectal cancer: a prospective randomized trial. J Clin Oncol (1995) 13, 1201–8.
Czejka MJ,Jäger W, Schüller J, Fogl U, Weiss C, Schernthaner G. Clinical pharmacokineticsof fluorouracil: influence of the biomodulating agents interferon, dipyridamole and folinic acidalone and in combination. Arzneimittelforschung (1993) 43, 387–90.