Atorvastatin Coadministration May Increase Digoxin Concentrations by Inhibition of Intestinal P-Glycoprotein-Mediated Secretion

Abstract

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

<i>In vitro</i> and <i>in situ</i> effects of atorvastatin and ezetimibe on P-glycoprotein expression and function

“…The P-gp substrate activity of atorvastatin was also suggested by some other studies (Williams and Feely, 2002;Wu et al, 2000). Boyd et al found that 100 µM atorvastatin inhibited digoxin secretion in Caco-2 cells (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the inhibition observed with verapamil (Boyd et al, 2000). Another study showed that atorvastatin increased the bioavailability of digoxin (Lennernäs, 2003), which may be explained by the inhibition of P-gp by atorvastatin.…”

“…Vatsa et al reported that atorvastatin is a moderate substrate for CYP P450 and is extensively metabolized via CYP P450-mediated oxidation and phase II glucuronidation both in humans and rats (Vatsa et al, 2012). The drug is a CYP3A4 substrate, and most of CYP3A4 substrates are P-gp substrates as well (Boyd et al, 2000). Vatsa et al stated that atorvastatin is a P-gp substrate at lower dose and an inhibitor at higher doses (Vatsa et al, 2012).…”

Köpeklerde Ketaminle İndüklenmiş Anestezi Üzerine Verapamilin İndüksiyon ve Rekover Özellikleri ve Kardiyorespiratuar Etkileri

“…It has also been shown that verapamil has a role on inhibition of P-glycoprotein (Pgp) which is a drug efflux pump. Inhibition of Pgp results in increased plasma level and subsequent longer duration of action of other drugs used with verapamil [14] . HR in SAL showed significant increases after induction of anaesthesia, which is remained high in the whole assessment period compared with the base.…”

Drug-drug Interactions of Statins Potentially Leading to Muscle-Related Side Effects in Hospitalized Patients

“…We had 4 pDDIs of digoxin used together with atorvastatin which could lead to an increase in plasma concentration of digoxin (up to 20%) and consequently digoxin's adverse reactions [27], 4 pDDIs of acenocoumarol and rosuvastatin which may result in increase of international normalized ratio (INR) and increased risk of bleeding [28] and 3 pDDIs of carbamazepine and atorvastatin (2 cases) and lovastatin (1 case) that could result in decreased exposure to the statin and consequently a lower efficacy. None of these pDDIs had clinical outcome.…”