ABSTRACT
Title
Effects of the Proton Pump Inhibitor Lansoprazole on the antiplatelet effect of naproxen in healthy subjects
Authors
P. Anzellotti1, ML. Capone1, S. Tacconelli1, A. Bruno1, V. Evangelista2, P. Di Gregorio3 and P. Patrignani1
1 Dept. of Medicine and Aging, “G.d’Annunzio” University and CeSI, Chieti (Italy);
2 Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy;
3 SS. Annunziata Hospital, Chieti, Italy.
1 Dept. of Medicine and Aging, “G.d’Annunzio” University and CeSI, Chieti (Italy);
2 Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy;
3 SS. Annunziata Hospital, Chieti, Italy.
Abstract
Naproxen is associated with a safer profile than other NSAIDs for the cardiovascular system, due to its profound suppression of platelet cyclooxygenase(COX)-1 activity, which persists throughout dosing interval for its long half-life(approximately 17h)(GarciaRodriguez et al., 2008). However, naproxen administration is associated with increased incidence of gastrointestinal toxicity(Masso Gonzalez et al., 2010) and it is advisable to administer at the lowest dose to control symptoms and to coadminister H,K-ATPase(called proton pump, PP) inhibitors(PPI) to patients with gastrointestinal intolerance(Sostres et al.,2010).Thus, lansoprazole is often coadministered with naproxen.
The aim of this study was to verify whether the coadministration of lansoprazole interferes with the inhibitory effects of low-dose naproxen(220 mg BID) on platelet COX-1 activity ex vivo in healthy subjects. Moreover, we explored the effects of lansoprozole and its active metabolite, AG2000 on platelet thromboxane(TX)B2 generation in vitro in washed human platelets.
We performed a crossover, open-label study in 6 healthy subjects(4 males, 2 females; they were between 23 and 30 years of age). They received consecutively: i)naproxen alone, ii)naproxen with lansoprazole, iii)lansoprazole alone iv)aspirin(100mg daily) for 6 days, separated by washout periods of two weeks. Whole blood samples were collected before and on day 6, at 1-24h after dosing to assess: i) the generation of TXB2 in whole blood, allowed to clot for 1h at 37°C, by a specific radioimmunoassay(Patrono et al., 1980)(serum TXB2 is a capacity index of platelet COX-1 activity); ii) naproxen plasma levels by HPLC(Capone et al., 2007). Moreover, we evaluated the effects of lansoprazole and its active metabolite, AG 2000, (1-1000 μM) on COX-1-dependent TXB2 generation in vitro by washed human platelets stimulated with thrombin(0,5 U/ml) and fibrinogen(0.38 mg/ml) for 45 min at 37°C. In some experiments platelets were pre-incubated with lansoprazole or AG2000 for 5 minutes, then washed and finally activated with thrombin.
Naproxen alone caused a maximal inhibition of serum TXB2 at 2h after dosing(96+2%, mean+SEM) which was slowly recovered. At 24h after dosing, it was 69+8%. The co-administration of naproxen with lansoprazole, caused a comparable inhibition of COX-1 activity at 2h(97+0.9%) versus naproxen alone. However, at 24h after dosing, serum TXB2 was more profoundly inhibited(90.4+1.4%, P<0.01) than naproxen alone. At 24h after dosing, aspirin caused a higher inhibition of platelet COX-1 activity than naproxen alone, but not of naproxen co-administered with lansoprazole(98.7+0.4%, P<0.01). The coadministration of lansoprazole did not affect naproxen plasma levels versus naproxen alone. Lansoprazole alone caused a small, but significant, inhibition of serum TXB2 by 20-30%. In washed platelets stimulated with thrombin, lansoprazole and its active metabolite AG2000 caused a concentration-dependent inhibition o TXB2 biosynthesis(IC50:360 and 40 μM, respectively). A significant(P<0.01) reduction of platelet TXB2 generation(40+8%) was detected at 1 μM of AG2000(a concentration reached in vivo). The reduction of TXB2 generation by lanzoprazole and AG2000 was partially recovered by platelet washing, thus suggesting the contribution of an irreversible mechanism.
In conclusion, the coadministration of lansoprazole potentiated the inhibition of platelet COX-1 activity by naproxen sodium 220mg BID.This effect did not involve the interference of lansoprazole with naproxen PK while it seems due to the capacity of lansoprazole and its active metabolite to affect thrombin-stimulated platelet TXA2 generation.
GarciaRodriguez et al.(2008). J Am Coll Cardiol.52,1628–36.
Masso Gonzalez et al.(2010). Arthritis Rheum 62,1592–601.
Sostres et al. (2010). Best Pract Res Clin Gastroenterol.24,121-32.
Patrono et al.(1980). Thromb Res.17,317-27.
Capone et al. (2007). J Pharmacol Exp Ther. 322:453-60.
The aim of this study was to verify whether the coadministration of lansoprazole interferes with the inhibitory effects of low-dose naproxen(220 mg BID) on platelet COX-1 activity ex vivo in healthy subjects. Moreover, we explored the effects of lansoprozole and its active metabolite, AG2000 on platelet thromboxane(TX)B2 generation in vitro in washed human platelets.
We performed a crossover, open-label study in 6 healthy subjects(4 males, 2 females; they were between 23 and 30 years of age). They received consecutively: i)naproxen alone, ii)naproxen with lansoprazole, iii)lansoprazole alone iv)aspirin(100mg daily) for 6 days, separated by washout periods of two weeks. Whole blood samples were collected before and on day 6, at 1-24h after dosing to assess: i) the generation of TXB2 in whole blood, allowed to clot for 1h at 37°C, by a specific radioimmunoassay(Patrono et al., 1980)(serum TXB2 is a capacity index of platelet COX-1 activity); ii) naproxen plasma levels by HPLC(Capone et al., 2007). Moreover, we evaluated the effects of lansoprazole and its active metabolite, AG 2000, (1-1000 μM) on COX-1-dependent TXB2 generation in vitro by washed human platelets stimulated with thrombin(0,5 U/ml) and fibrinogen(0.38 mg/ml) for 45 min at 37°C. In some experiments platelets were pre-incubated with lansoprazole or AG2000 for 5 minutes, then washed and finally activated with thrombin.
Naproxen alone caused a maximal inhibition of serum TXB2 at 2h after dosing(96+2%, mean+SEM) which was slowly recovered. At 24h after dosing, it was 69+8%. The co-administration of naproxen with lansoprazole, caused a comparable inhibition of COX-1 activity at 2h(97+0.9%) versus naproxen alone. However, at 24h after dosing, serum TXB2 was more profoundly inhibited(90.4+1.4%, P<0.01) than naproxen alone. At 24h after dosing, aspirin caused a higher inhibition of platelet COX-1 activity than naproxen alone, but not of naproxen co-administered with lansoprazole(98.7+0.4%, P<0.01). The coadministration of lansoprazole did not affect naproxen plasma levels versus naproxen alone. Lansoprazole alone caused a small, but significant, inhibition of serum TXB2 by 20-30%. In washed platelets stimulated with thrombin, lansoprazole and its active metabolite AG2000 caused a concentration-dependent inhibition o TXB2 biosynthesis(IC50:360 and 40 μM, respectively). A significant(P<0.01) reduction of platelet TXB2 generation(40+8%) was detected at 1 μM of AG2000(a concentration reached in vivo). The reduction of TXB2 generation by lanzoprazole and AG2000 was partially recovered by platelet washing, thus suggesting the contribution of an irreversible mechanism.
In conclusion, the coadministration of lansoprazole potentiated the inhibition of platelet COX-1 activity by naproxen sodium 220mg BID.This effect did not involve the interference of lansoprazole with naproxen PK while it seems due to the capacity of lansoprazole and its active metabolite to affect thrombin-stimulated platelet TXA2 generation.
GarciaRodriguez et al.(2008). J Am Coll Cardiol.52,1628–36.
Masso Gonzalez et al.(2010). Arthritis Rheum 62,1592–601.
Sostres et al. (2010). Best Pract Res Clin Gastroenterol.24,121-32.
Patrono et al.(1980). Thromb Res.17,317-27.
Capone et al. (2007). J Pharmacol Exp Ther. 322:453-60.