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Tolerance to glyceryl trinitrate (GTN) was developed in healthy volunteers by treatment with GTN patches, 10 mg/24 h. The difference (supine position-erect position) in systolic blood pressure (SBP) observed after application of GTN patches at the first day disappeared after 24-h transdermal administration for 2-4 consecutive days, indicating that tolerance to GTN had developed in the group of 12 healthy volunteers treated with active drug. Increased HR during the first day also disappeared as a sign of tolerance development to GTN. The phosphodiesterase (PDE) inhibitor dipyridamole (Dip) showed no effect on SBP in either the GTN-tolerant group or in the placebo group, and the tolerance to GTN was not reversed. The present study shows that addition of Dip to GTN cannot reverse GTN tolerance. Plasma concentrations of GTN and its two dinitrate metabolites were measured after transdermal administration. Addition of Dip to GTN showed no influence on the pharmacokinetics of the nitrates in healthy volunteers.

To determine whether repeated once daily administration of grapefruit juice altered the pharmacokinetics or pharmacodynamics of the calcium antagonist amlodipine.S The effects of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral and intravenous amlodipine were assessed in 20 healthy men in a placebo-controlled, open, randomized, four-way crossover study using single doses of amlodipine 10 mg. For 9 days beginning with the day of administration of amlodipine, grapefruit juice (or water control) was given once daily, and blood samples, blood pressure and heart rate measures were obtained. Plasma concentrations of amlodipine and its enantiomers were determined in separate assays by GC-ECD.Oral amlodipine had high systemic availability (grapefruit juice: 88%; water: 81%). Pharmacokinetic parameters of racemic amlodipine (AUC, Cmax, tmax, and kel) were not markedly changed with grapefruit juice coadministration. Total plasma clearance and volume of distribution, calculated after intravenous amlodipine, were essentially unchanged by grapefruit juice (CL 6.65 ml min-1 kg-1, juice vs 6.93 ml min-1 kg-1, water; Vdss 22.7 l kg-1, juice vs 21.0 l kg-1, water). Grapefruit juice coadministration did not greatly alter the stereoselectivity in amlodipine oral or intravenous kinetics. The sum of S(-) and R(+) enantiomer concentrations correlated well with total racemic amlodipine concentration (r2 = 0. 957; P = 0.0001). Coadministration of grapefruit juice with either route of amlodipine administration did not significantly alter blood pressure changes vs control.Grapefruit juice has no appreciable effect on amlodipine pharmacodynamics or pharmacokinetics, including its stereoselective kinetics. Bioavailability enhancement by grapefruit juice, noted with other dihydropyridine calcium antagonists, does not occur with amlodipine. Once daily grapefruit juice administration with usual oral doses of amlodipine is unlikely to alter the profile of response in clinical practice.