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Hemodynamic effects of glucagon: A literature review

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This allows them to bypass metabolism by hepatic enzymes such as CYPs or UDP-glucuronosyltransferases (UGTs).121123 Consequently, drug-metabolizing enzyme-mediated DDIs, typically involving competition for the same CYP binding site with another drug, are uncommon in peptide drug-related DDIs.124 Moreover, many peptide drugs are not known to be substrates or inhibitors of transporters at present, indicating that transporter-mediated biliary or renal excretion may not be a major pathway for their elimination.124 Therefore, it was speculated that peptide drugs are unlikely to be involved in the occurrence of transporter-mediated DDIs.122,124 However, increasing evidence is reporting the involvement of peptide drugs in the occurrence of CYP or transporter-mediated DDIs.123 The native glucagon peptide stimulates cAMP production, and elevated cAMP levels in rat hepatocytes indirectly reduce CYP2C11 expression.125 Moreover, research indicates that growth hormone enhances CYP3A4 expression in human hepatocytes, while synthetic somatostatin analogs like octreotide, which inhibit endogenous growth hormone, may decrease CYP3A4 activity.126 Co-administration of warfarin (a substrate of CYP1A2, CYP2C9, and CYP3A4) and octreotide led to high INR levels in humans, which may be attributed to the increased warfarin exposure caused by octreotides inhibitory effect on CYP3A4.127 Additionally, cyclosporine is an 11 aa-long lipophilic cyclic polypeptide used as an immunosuppressant.128 Cyclosporine has been identified as a substrate for CYP3A4, P-glycoprotein (P-gp), and organic anion transporting polypeptides (OATPs), while also acting as a potent inhibitor of CYP3A4, multidrug resistance-associated protein 2 (MRP2), OATPs, P-gp, and breast cancer resistance protein (BCRP).129131 Cyclosporine was found to inhibit CYP3A4 with a K i of 1.42 M in human liver microsomes, and systemic exposure of atorvastatin increased 15-fold in humans with the co-administration of cyclosporine.132,133 A recent in vitro DDI study of ATSP-7041, a stapled -helical peptide being developed as an anticancer agent, revealed minimal CYP inhibition