Which cytochrome P450 enzyme is primarily responsible for the conversion of codeine to its active metabolite, morphine?

The cytochrome P450 enzyme primarily responsible for the conversion of codeine to its active metabolite, morphine, is CYP2D6. Cytochrome P450 enzymes are a superfamily of enzymes involved in the metabolism of many drugs, including opioids. Codeine itself has relatively low affinity for opioid receptors and is considered a prodrug, meaning it needs to be metabolized into a more active form to exert its analgesic effects. CYP2D6 performs O-demethylation of codeine, which removes a methyl group and converts it into morphine. Morphine has a significantly higher affinity for the mu (μ) opioid receptor than codeine, making it much more effective as an analgesic. Genetic polymorphisms, or variations, in the CYP2D6 gene can significantly affect an individual's ability to metabolize codeine into morphine. Individuals with increased CYP2D6 activity ('ultrarapid metabolizers') may convert codeine to morphine very efficiently, leading to enhanced analgesic effects or, in some cases, increased risk of adverse effects. Conversely, individuals with reduced or absent CYP2D6 activity ('poor metabolizers') will convert very little codeine into morphine, resulting in reduced analgesic efficacy. Therefore, CYP2D6 is critical for the activation of codeine, and individual differences in CYP2D6 activity can significantly impact the drug's effectiveness and safety.