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Metabolic Interactions Between Over-the-counter and Illicit Drugs at Cytochrome P450

Crosswy, Kara Kelley
Abstract
Drug- drug interactions between over- the- counter (OTC) and scheduled drugs may occur at cytochrome P450, which can lead to toxicity and possibly death. This study examined the effects of two OTC drugs, cimetidine (CMT) and dextromethorphan (DEX), and two scheduled drugs, methamphetamine (MA) and 3, 4-methylenedioxymethamphetamine (MDMA) at CYP2D6. Purified human CYP2D6 was used to determine the inhibitory potential (IC50) of the drugs in vitro. This assay examined the conversion of AMMC to its fluorescent metabolite product, AHMC. Enzyme kinetics was conducted to determine Vmax and Km values in vivo using rat microsome CYP2D2 isozyme. Solid phase extraction was used to extract MA from liver supernatant using Varian Bond Elut columns. GC/ MS was performed on the extracted MA samples to examine changes in MA metabolism following exposure to CMT or DEX. Findings and Conclusions: In vitro, the IC50 values for the test compounds and CYP2D6 activity were not different compared to quinidine IC50 value. Maximum inhibition of CYP2D6 activity in the presence of test compounds [CMT, CMT/ MA, DEX/ MA, DEX/ MDMA, CMT/ DEX/ MA and CMT/ DEX/ MDMA] compared to maximum quinidine inhibition decreased significantly from quinidine and CMT/ MDMA inhibition, a 75-85% decrease compared to quinidine. Maximum MA inhibition was significantly decreased compared to maximum quinidine inhibition. This data suggests that all the test compounds inhibited CYP2D6 activity; one or all of the drugs may not be metabolized as quickly resulting in toxicity of those drugs. In vivo CYP2D2 studies showed that the Vmax value in the CMT treated group (98.28 + 22.09 pmol/ mg protein/ min) increased significantly compared to naive (19.92 + 5.084 pmol/ mg protein/ min). The Km value in the saline (6.806 + 0.73 ?M) and CMT (6.728 + 1.341 ?M) treated groups increased significantly compared to naive (3.081 + 0.46 ?M). All MA challenged groups showed increases in Vmax (280- 490%) and Km (165- 220%) values compared to the naive group. Therefore, MA challenge resulted in an increase in both kinetic parameters (Vmax and Km) suggesting that the low affinity/ high capacity CYP2D2 isoform was upregulated. This data suggests that MA is an inducer via CYP2D2, which will lead to altered drug metabolism and an alteration of the drug's effects.
Date
2007-12-01
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