Mechanistic Inhibition of Opioid Metabolism

Illicit opioid abuse and ensuing mortality has substantially increased over the past decade in the U.S. Sources of opioid use include prescription pain medications, substitute therapies, and illicit drugs. Buprenorphine is part of the mixed narcotic agonist-antagonists drug class and is used to treat opioid dependence among individuals. Another class of drugs referred to as Proton Pump Inhibitors (PPI) are commonly prescribed to individuals in order to reduce gastric acid production. Drug-drug interactions may occur when Buprenorphine and a PPI are prescribed simultaneously, inhibiting the body’s cytochrome P450 family enzymes from breaking down the drugs into sub-toxic levels. The cytochrome P450 family enzymes are xenobiotic metabolizing enzymes located in the liver, small intestine, and large intestine. These enzymes are mainly comprised of a polypeptide chain and heme cofactor. Once the heme binds with oxygen, cytochrome P450 utilizes nicotinamide adenine dinucleotide phosphate (NADPH) as an H+ energy source for oxidation of buprenorphine via the NADPH-cytochrome P450 oxidoreductase. Therefore, NADPH acts as the energy source for studying the drug interactions of Buprenorphine and Proton-Pump Inhibitors. Our objective was to study the time-dependent inhibition that Cimetidine and Rabeprazole, both proton pump inhibitors, have on the metabolism of buprenorphine via the cytochrome P450 enzymes