Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

Abstract

Purpose The organic cation transporters (OCTs) and multi-drug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs. Methods The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice. Results The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice. Conclusions Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.

Pharmacokinetics of Organic Cation Transporter 1 (OCT1) Substrates in Oct1/2 Knockout Mice and Species Difference in Hepatic OCT1-Mediated Uptake

“…The IC 50 for OCT1 was 608 mM and for OCT2 was 0.14 mM. As reported previously (Kido et al, 2011;Zhu et al, 2018), potent OCT inhibition was observed by imipramine and verapamil; IC 50 values for OCT1 were 0.67 and 10.1 mM, respectively, and were 0.14 and 0.11 mM for OCT2 (data not shown). After accounting for the effect of all three inhibitors in VC cells, the ratios of uptake in OCT1 cells with/without inhibitor over VC cells with/without inhibitor are consistent with each inhibitor, and represent the effect of each inhibitor specifically on OCT1-mediated uptake, shown in Fig.…”

Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

“…Therefore, inclusion of these transporters could be important for modeling oral dosing data, which was not the focus in this study. In addition, studies in HEK293‐OCT2 cells suggest that morphine is a substrate of the renal transporter OCT2 48 . However, the influence of OCT2 on morphine disposition is expected to be low because only < 10% of morphine is recovered unchanged in urine 20,21 .…”

“…In addition, studies in HEK293-OCT2 cells suggest that morphine is a substrate of the renal transporter OCT2. 48 However, the influence of OCT2 on morphine disposition is expected to be low because only < 10% of morphine is recovered unchanged in urine. 20,21 Although M3G is not a substrate of OATP2B1, 48 data from uptake studies in hepatocytes suggest that OATP1B transporters are involved in M3G uptake into the liver.…”

“…48 However, the influence of OCT2 on morphine disposition is expected to be low because only < 10% of morphine is recovered unchanged in urine. 20,21 Although M3G is not a substrate of OATP2B1, 48 data from uptake studies in hepatocytes suggest that OATP1B transporters are involved in M3G uptake into the liver. 11 The significance of OATP1B transporters, which are altered in NASH, 9,11,12,15 on M3G disposition in healthy subjects and in NASH remains to be further evaluated to address identifiability issues between OATP1B uptake and MRP3 efflux at the hepatic basolateral membrane.…”

Bridging the gap betweenin silicoandin vivo:modeling opioid disposition in a kidney proximal tubule microphysiological system

“…With the increased risk of opioid overdose and adverse events in people with CKD 12 transporters (OCTs) in the hepatic uptake is recognized (36,37). The present study utilized a VPT-MPS to evaluate the kidney secretion of morphine and M6G and to predict kidney clearance of these compounds in humans.…”