Morphine and loperamide are μ opioid receptor agonists with a long history of clinical use worldwide. Morphine is an analgesic drug widely used to alleviate cancer-related pain. It can be taken orally, is absorbed in the intestine, and permeates into the brain, where it binds μ opioid receptors to exert its central pharmacological effect. Further,
morphine peripherally binds to the intestinal μ opioid receptors, causing constipation (an adverse effect of morphine). Loperamide is an antidiarrheal agent that exerts its pharmacological activity by agonistically binding to μ opioid receptors in the intestine, similar to the mechanism of morphine’s adverse effect. However, it has little or no central pharmacological effect because it does not readily permeate into the brain. The difference in the pharmacological effects of morphine and loperamide can be attributed to the differences in their tissue distributions. The degree of interaction of each drug with P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may explain this difference. P-gp is a transmembrane adenosine triphosphate (ATP)- driven efflux pump encoded by multidrug resistance gene (MDR1 or ABCB1). It is mainly expressed in the transporting epithelia of various human tissues, including the intestine, liver, kidney, and BBB, where it actively transports its substrates out of the cell. P-gp substrates include major antiarrhythmics (verapamil and bepridil); anticoagulants (apixaban, dabigatran, and propranolol); and antihypertensive drugs (aliskiren, diltiazem, losartan, and talinolol); immunosuppressive calcineurin inhibitors cyclosporine and tacrolimus; and narcotic analgesic morphine; however, the contribution of P-gp to the total amount of intestinal absorption varies.
Loperamide is a high-affinity P-gp substrate. It is effectively pumped out by P-gp at the BBB; thus, pharmacologically effective concentrations are not achieved in the brain. Morphine is also suggested to be a substrate of P-gp, because it has been shown to produce greater analgesia in P-gp-knockout mice than in wild-type mice; however, morphine disposition is not considered critically dependent on P-gp. P-gp is expressed in the small intestine as well as the BBB.
In the small intestine, P-gp limits the absorption of certain drugs. The pharmacokinetics of digoxin is affected by the function of P-gp in the intestine. Intestinal P-gp limits the oral bioavailability and active epithelial excretion of paclitaxel, as demonstrated by using mdr1a-knockout mice. In rats, several β-blockers are actively secreted from the small intestinal epithelium into the lumen by P-gp, which functions as an absorption barrier, resulting in decreased blood concentrations of these drugs. In addition, the absorptive transport of the serotonin antagonist azasetron is regulated by P-gp in vitro. Intestinal transport of pitavastatin is mediated by efflux transporters such as not only P-gp but also another transporter, organic anion transporting polypeptide, as. We demonstrated that the intestinal transport of quinolone antimicrobials is regulated by P-gp in rat intestinal tissue and human intestinal cell line Caco-2. Considering its important role in intestinal absorption, P-gp could influence the absorption of opioids in the small intestine. However, the mechanisms of the intestinal absorption of such drugs and the role of intestinal P-gp in their absorption have not yet been directly demonstrated. In this study, we aimed to examine the intestinal transport characteristics of morphine and loperamide by using Caco-2 cells and rat small intestinal tissues and the role of P-gp in their transport by performing inhibition studies with rhodamine 123 and cyclosporine A (CsA).
