Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics

Abstract

The bioavailability of some dihydropyridine calcium antagonists can be markedly augmented by grapefruit juice and may involve the bioflavonoid naringin. The pharmacokinetics of nisoldipine coat-core tablet were studied in a Latin square-designed trial in which 12 healthy men were administered the drug with water, grapefruit juice, or encapsulated naringin powder at the same amount as that assayed in the juice. Compared with water, grapefruit juice increased the maximum concentration of nisoldipine to 406% +/- 73% (mean +/- SEM; range, 107% to 836%; p < 0.001), increased the area under the plasma concentration-time curve to 198% +/- 46% (range, 81% to 682%; p < 0.001), and reduced time to reach maximum nisoldipine concentration to 58% +/- 9% (range, 13% to 100%; p < 0.01), probably by inhibition of presystemic metabolism and possibly by enhancement of drug dissolution. The interaction could not be predicted from baseline pharmacokinetics with water and resulted in greater interindividual variability. The naringin capsule did not change nisoldipine pharmacokinetics. All treatments produced minor effects on supine blood pressure and heart rate, probably because subjects were normotensive. Current information supports the cautioning of patients about concomitant ingestion of grapefruit juice and nisoldipine.

Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance

“…Most of these studies reported further decreases in diastolic blood pressure when felodipine was taken with grapefruit juice, as well as increase in haemodynamic-related adverse effects such as increased heart rate and orthostatic hypotension (Bailey et al, 1991;Lundahl et al, 1997Lundahl et al, , 1998. Other dihydropyridines exhibiting the interaction to a similar extent are nisoldipine (Bailey et al, 1993b;Takanaga et al, 2000) and nicardipine . A milder but significant interaction has been detected with nitrendipine, pranidipine and nimodipine that exhibited bioavailability increments of 100, 73 and 50%, respectively (Soons et al, 1991;Fuhr et al, 1998;Hashimoto et al, 1998).…”

“…In addition, in studies that were performed on liver microsomes, naringenin, naringin's aglycon metabolite, showed the ability to inhibit dihydropyridine metabolism in vitro (Miniscalco et al, 1992). However, in vivo studies using isolated naringin have not shown reduced metabolism of CYP3A4 substrates (Bailey et al, 1993b). Also, grapefruit juice itself shows inhibition in vitro under conditions that do not allow the formation of naringenin (Edwards & Bernier, 1996).…”

Modeling of Intestinal Drug Absorption: Roles of Transporters and Metabolic Enzymes (For the Gillette Review Series)

“…Moreover, these models do not relate to blood flow, drug partitioning, and the phenomenon of route-dependent intestinal metabolism. A greater understanding of the interplay will allow sound interpretations on intestinal drug metabolism and transport with respect to other drugs or the intake of fruit juices (Bailey et al, 1993;Lown et al, 1997a;Dresser et al, 2002).…”

The Use of Heat Treatment to Eliminate Drug Interactions Due to Grapefruit Juice

“…15) In fact, unlike GJ, naringin, a potent, but not mechanism-based inhibitor of CYP3A, 21) has been reported not to increase the availability of nisoldipine in humans. 26) The present investigations clearly showed the contributions of FCs on drug interactions with GJ in in vitro and in vivo experiments using GJ samples, eliminated BG and DHB following high temperature treatments. Furthermore, these observations may develop as fundamental knowledge to create "drinkable GJ" for patients receiving medications that induce interactions with GJ.…”