Effect of codeine on CYP450 isoform activity of rats

Shuanghu Wang,Yanwen Dong,Ke Su,Jing Zhang,Linyi Wang,Anyue Han,Congcong Wen,Xianqin Wang,Yan He

doi:10.1080/13880209.2017.1297466

Shuanghu Wang, Yanwen Dong + Show 7 more

Open Access

https://doi.org/10.1080/13880209.2017.1297466

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Abstract

Context: Codeine, also known as 3-methylmorphine, is an opiate used to treat pain, as a cough medicine and for diarrhoea. No study on the effects of codeine on the metabolic capacity of CYP enzyme is reported.Objective: In order to investigate the effects of codeine on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of CYP2B1, CYP2D1, CYP1A2, CYP3A2 and CYP2C11.Materials and methods: Sprague–Dawley rats were randomly divided into codeine group (low, medium, high) and control group. The codeine group rats were given 4, 8, 16 mg/kg (low, medium, high) codeine by continuous intragastric administration for 14 days. Five probe drugs bupropion, metroprolol, phenacetin, midazolam and tolbutamide were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS.Results and conclusion: The pharmacokinetic parameters of bupropion and metroprolol experienced obvious change with AUC(0-t), Cmax increased and CL decreased for bupropion in medium dosage group and midazolam low dosage group. This result indicates that the 14 day-intragastric administration of codeine may inhibit the metabolism of bupropion (CYP2B1) and midazolam (CYP3A2) in rat. Additional, there are no statistical differences for albumin (ALB), alkaline phosphatase (ALP), creatinine (Cr) after 14 intragastric administration of codeine, while alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid (UA) increased compared to control group. The biomedical test results show continuous 14 day-intragastric administration of codeine would cause liver damage.

Highlights

Codeine, known as 3-methylmorphine, is an opiate used to treat pain (Havig et al 2016; Hudak 2016; Kimergard et al 2016), as a cough medicine, and for diarrhoea (Prommer 2011)
The blood was collected from the tail vein for biochemical tests of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), alkaline phosphatase (ALP), creatinine (Cr), uric acid (UA)
At 15 days morning, five probe drugs bupropion, metroprolol, phenacetin, midazolam and tolbutamide were mixed in corn oil and given to the rats of three codeine groups and control group by intragastric administration at a single dosage 10 mg/kg for bupropion, metroprolol, phenacetin, midazolam, 0.1 mg/kg for tolbutamide

Summary

Introduction

Known as 3-methylmorphine, is an opiate used to treat pain (Havig et al 2016; Hudak 2016; Kimergard et al 2016), as a cough medicine, and for diarrhoea (Prommer 2011). It is typically used to treat mild to moderate degrees of pain. Codeine is used to treat diarrhoea and diarrhoea-predominant irritable bowel syndrome, loperamide, diphenoxylate, paregoric or even laudanumare more frequently used to treat severe diarrhoea. There is weak evidence that it is useful in cancer pain but it is associated with increased side effects. Common adverse effects associated with the use of codeine include drowsiness and constipation. Longerterm effects can vary, but can include diminished libido, apathy and memory loss. Some people may have an allergic reaction to codeine, such as the swelling of skin and rashes

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