3.1. Absorption and excretion
Pgp is found on the different barriers that limit the passage of xenobiotics into the organism. Pgp is described as an important mechanism decreasing the bioavailability of oral drugs by limiting intestinal absorption (Aungst, 1999, Suzuki and Sugiyama, 2000 and Napoli et al., 1998). Moreover, Pgp can directly eluate drugs from the general circulation into the bile and intestinal lumen via hepatocytes and enterocytes, respectively (Sparreboom et al., 1997 and Schinkel and Jonker, 2003). Thus it can be supposed that compounds able to interact with Pgp activity could induce important modifications of bioavailability for numerous concomitantly administered drugs. Compounds able to modulate or inhibit Pgp activity would increase xenobiotic levels and also Pgp substrates (van Asperen et al., 1997). Pgp has also been observed in the brush border membrane of the proximal renal tubule (Thiebaut et al., 1987), and in vitro tests and pharmacological analyses on perfused animal kidneys have confirmed the implication of Pgp in the renal excretion of drugs. But studies on knock out mice (mdr1a−/−/mdr1b−/−) have presented rather contradictory results, probably because of differential gene regulations in these animal models (Lin, 2003 and Schinkel and Jonker, 2003).
Numerous drug–drug interactions as the digoxin/quinidine interaction are well documented in literature, but mechanisms remain badly understood. Roles of efflux proteins in these interactions may probably be important. Substances as quinidine, clarithromycin and propafenone reduce the renal secretion of digoxin by blocking Pgp activity in the renal tubule. In addition, quinidine interacts with digoxin absorption in the small intestine of rats. These two mechanisms lead to an increase in serum digoxin levels (Su and Huang, 1996, Wakasugi et al., 1998 and Woodland et al., 1997). The interaction between quinidine and digoxin is directly linked to Pgp inhibition, confirmed by the fact that in knock out mice (mdr1a−/−), digoxin plasma levels are not modified by quinidine, whereas in wild-type mice, quinidine significantly increases plasma digoxin levels by 73% (Fromm et al., 1999). In the same way, ritonavir, which is a potent inhibitor of cytochrome P450 isozymes and also of Pgp, is able to significantly enhance (1.86-fold) the area under the plasma concentration–time curve of digoxin in healthy patients taking ritonavir orally on a long-term basis (until therapeutic steady state) and intravenous digoxin. This interaction is a consequence of renal digoxin clearance inhibition, the result of Pgp inhibition by ritonavir (Ding et al., 2004).
The beta-blocker, talinolol, is also a Pgp substrate whose concentration–time profile is modified by a concomitant administration of Pgp inhibitors. It has been showed that verapamil in rats (Spahn-Langguth et al., 1998) and erythromycin in humans (Schwarz et al., 2000) can down-modulate the intestinal Pgp activity and thus increase intestinal absorption of talinolol resulting in a greater oral bioavailability.
The class of proton pump inhibitors is known to interact with drug metabolising enzymes. A recent in vitro study has clearly demonstrated that omeprazole, lansoprazole and pantoprazole are substrates and inhibitors of Pgp and are able to down-modulate digoxin efflux (Pauli-Magnus et al., 2001). A serious case of rhabdomyolysis was reported in a patient taking atorvastatin, esomeprazole and clarithromycin. Although clarithromycin is a powerful inhibitor of CYP3A4, which metabolises atorvastatin, the antibiotic was introduced only during a short period following appearance of the first symptoms. The authors suspected a Pgp inhibition by esomeprazole, which decreases atorvastatin clearance (Sipe et al., 2003). These data supply further information to explain some of the well-known drug–drug interactions with proton pump inhibitors (Pauli-Magnus et al., 2001).
In addition, it may be emphasized that some excipients used in pharmaceutical formulations can interfere with Pgp activity and thus can interact with drug absorption and bioavailability. Two clinical studies using cremophors that make it possible to solubilise some liposoluble drug substances, have demonstrated their capacity to interact with Pgp activity. Effectively, cremophor EL and cremophor RH 40 are able to increase the oral absorption and thus the bioavailability of saquinavir and digoxin, respectively (Martin-Facklam et al., 2002 and Tayrouz et al., 2003). Other excipients, such as Tween 80 and solutol HS15, are also able to inhibit Pgp activity and to increase daunorubicin intracellular levels in cell cultures (Woodcock et al., 1992). Moreover, some lipids limit Pgp efflux through the intestinal wall in the gut lumen (Wasan, 2001). With such data, the role of excipients contained in drug formulations must be emphasized, which can be a source of drug–drug interactions in administered therapies.
Food can also interact with Pgp. For example, grapefruit juice, a well-known enzymatic inhibitor of cytochrome P450 that leads to increased bioavailability of co-administered drugs, is implicated in interactions with Pgp, although with rather contradictory results. Three studies made evident an inhibition of Pgp activity by grapefruit juice on Pgp expressing cell cultures, that increased vinblastine and talinolol cell levels (Wang et al., 2001, Takanaga et al., 1998 and Spahn-Langguth and Langguth, 2001). In a study in rats, similar results were observed, such as an increased talinolol absorption following concomitant administration of grapefruit juice (Spahn-Langguth and Langguth, 2001). However, different results were supplied by Soldner et al. (1999), which showed that grapefruit juice stimulated Pgp activity and increased efflux of xenobiotics. In humans, grapefruit juice does not seem to have a significant effect on human Pgp activity (Becquemont et al., 2001). Different varieties of garlic have a mild effect on Pgp activity compared to verapamil, whereas they showed a potential inhibitory effect on cytochrome P450 (Foster et al., 2001). Other dietary constituents are possibly Pgp modulators. Piperine, a major component of black pepper, is also able to down-modulate efflux protein activity like Pgp and inhibit digoxin and cyclosporin A transport in Pgp overexpressing cells (Bhardwaj et al., 2002). Curcumin, a natural compound of Curcuma longa down-modulates both in vitro expression and function of hepatic Pgp (Romiti et al., 1998 and Anuchapreeda et al., 2002). Another natural compound is ginsenoside Rg3, derived from red ginseng, which increases vinblastine cellular accumulation inhibiting Pgp activity on Pgp expressing cells (Kim et al., 2003). These food–drug interactions can, however, have serious consequences on therapeutic use. Thus concomitant administration of quercetin, an ubiquitous flavonoid distributed in various plants (e.g. tea, St. John s wort and ginkgo) and digoxin (0.02 mg/kg, p.o.) to pigs was responsible for a dramatic increase in digoxin levels leading to toxicity and death of two of the three co-treated animals (Wang et al., 2004).
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