The Role of P-Glycoprotein and Organic Anion-Transporting Polypeptides in Drug Interactions

Abstract

The use of polytherapy in clinical practice necessitates an appreciation and understanding of the potential for drug interactions. Recent publications provide insight into the role of the active transport systems P-glycoprotein (P-gp) and human organic anion-transporting polypeptides (OATPs) in drug interactions. Active drug transporters influence the bioavailability of a number of drugs by controlling their movement into, and out of, cells. The active transport systems P-gp and OATP play an important role in drug elimination. The activity of these transport systems is controlled, in part, by genetic factors; however, drugs and foods also influence the activity of these systems. It appears that interference with P-gp or OATP, either as upregulation or inhibition, may affect plasma drug concentrations by altering intestinal absorption, proximal renal-tubular excretion or biliary excretion. Overall, the net bioavailability of a drug or substance is affected by the relative contributions of cellular efflux (P-gp) and influx (OATP) mechanisms and to what extent these systems are active during phases of uptake and absorption versus removal and excretion from the body. Many of the drugs and foods that affect active drug transport activity are known to interact with the cytochrome P450 enzyme system; therefore, the net effect of concomitant drug administration is complex. One must now consider the impact of metabolism (CYP-mediated drug biotransformation), P-gp-mediated drug efflux and OATP-mediated uptake when making assessments of drug absorption and distribution.

Rifaximin as a rare cause of rhabdomyolysis in cirrhosis

“…The reasons behind this are multifactorial, including increased intestinal permeability due to alterations in the mucosal barrier, inflammation, and changes in the gut microbiota 6. Cirrhosis also alters the functional ability of p‐glycoprotein, an important efflux pump that transports drugs and toxins out of cells and into the GI lumen, renal tubule, and bile duct 7. Further caution must also be taken with concomitant use of p‐glycoprotein inhibitors, such as statins and spironolactone, medications commonly prescribed to cirrhotic patients 8.…”

Les nouveaux anticoagulants oraux

“…L'héparine non fractionnée (HNF) et les héparines de bas poids moléculaire (HBPM) sont des mélanges de chaînes polysaccharidiques plus ou moins longues extraites de muqueuse intestinale de porc. Les AVK bloquent le mécanisme de réduction de la vitamine K 1 , un cofacteur de la synthèse hépatique de quatre pro-transport transmembranaires de type P-glycoprotéines (P-gp) qui régulent sa concentration plasmatique [2]. Ainsi des médicaments inhibiteurs ou activateurs de P-gp peuvent interférer avec la concentration plasmatique du dabigatran étexilate (Tableau I).…”

“…Celui des AVK étant plus long, ceux-ci ne sont que rarement utilisés en première intention. Une surveillance biologique attentive mais contraignante de ces traitements est requise 2 . De plus, la cible thérapeutique des AVK est particulièrement étroite et de nombreuses interférences médicamenteuses ou alimentaires rendent difficile l'équilibration du traitement.…”

“…Ce sont principalement des inhibiteurs spécifiques ciblés sur un seul facteur de la coagulation, tels la thrombine ou le facteur X activé (a). 2 Cette surveillance se fait par la mesure de l'INR pour les AVK. Les contrôles d'INR ont lieu, lorsque le traitement par AVK est équilibré (soit un délai en général de 8 jours après l'instauration), toutes les semaines, puis tous les 15 jours, puis une fois par mois.…”

Pharmacokinetics and Drug Interactions of Herbal Medicines: A Missing Critical Step in the Phytomedicine/Drug Development Process

“…Drugs that are substrates of CYP3A4 often affect P-glycoproteins as well (73), thus the interplay of both intestinal P-gp and CYP3A4 has a strong effect on the bioavailability of most orally administered drugs including proton pump inhibitors (PPIs), cyclosporine, midazolam, talinolol, statins, HIV protease inhibitors and verapamil (74,75,76). Therefore concomitant intake of herbal medicinal products that are P-gp and/or CYP3A4 substrates with othodox drugs has a higher potential for interaction.…”