Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response
Journal Title: Toxicology and Forensic Medicine – Open Journal - Year 2017, Vol 2, Issue 2
Abstract
Aim: To determine the interaction of over-the-counter (OTC) and illicit psychostimulants at the cytochrome P450 enzyme, CYP2D6. CYP2D6 is responsible for 20% of hepatic Phase I metabolism and is a site of drug-drug interactions, leading to increased drug toxicity. Materials and Methods: We examined the effects the OTC drugs; 1) the prototype H2-antagonist cimetidine (CMT) and 2) the opioid agonist cough suppressant dextromethorphan (DEX); as well as two scheduled drugs, methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) for their ability to interfere with CYP2D6 activity. Assays with human CYP2D6 determined the inhibitory potential (IC50) of each drug. Kinetic analysis (Vmax and Km) was accomplished using rodent hepatic microsomes. Results: Maximum inhibition of CYP2D6 activity following exposure to CMT+MDMA was significantly reduced 75-85% compared to quinidine (control) values. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Assays using rat CYP2D2 demonstrated Vmax elevations in the CMT group (493%) compared to control (naïve, no treatment) values (19.9±5.1 pmol/mg protein/min). The Km was increased 218% in CMT compared to controls (3.1±0.5 μM). Collectively, all MA challenged groups exhibited increases in total enzyme [Vmax; 280-490%] and affinity [Km; 165-220%] values compared to the control group. The increase in both Vmax and Km suggests that the low affinity/high capacity CYP2D2 isoform is upregulated. Conclusion: Our findings suggest that in vivo, MA acts as a CYP2D2-inducer, which will lead to altered secondary drug metabolism, increasing the risk of drug-related toxicity. Coupled with the ability of CMT and DEX to interfere with MA metabolism, a complex drug-drug interaction is possible, leading to increased toxicity. Our findings substantiate the hypothesis that the combination of illicit and OTC drugs could result in complex drug-drug interactions increasing the risk for severe drug-related toxicity.
Authors and Affiliations
David R. Wallace
Keywords
Related Articles
- EP ID EP550817
- DOI 10.17140/TFMOJ-2-120
- Views 159
- Downloads 0
Toxicity of Antioxidants
The fundament of toxicology is the risk-benefit analysis. This means that the positive as well as the negative health effects of all compounds, including antioxidants, have to be assessed and related to each other. Only...
Hyperhomocysteinemia and Alcoholism: A Double Hit?
Homocysteine (HCY) is a non-protein sulfur-containing amino acid. It has received a great deal of attention over the last two decades within the scientific community for its unique role in the induction of several diseas...
Effects of Exposure to Cypermethrin on the Onset of Puberty and Ovarian Biomarkers in Female Prepubertal Rat: Attenuating Role of Zinc
Cypermethrin, a synthetic pyrethyroid pesticide, is used for more than one decade to control a wide variety of pests in agriculture. The present study designed to evaluate the protective role of zinc in attenuating cyper...
Hepatotoxic-Microcystins in Two Drinking Water Reservoirs in the Central Region of Ghana
Background: Microcystins are cyclic peptides containing seven amino acids with the condensation of two terminal amino acids of the linear peptide to form a cyclic compound. The cyclic nature of microcystins suggests that...
Forensic Toxicology: The Dangers of Chasing the Single Molecule
On depictions dating from the Middle Ages, physicians are often shown holding a glass with a yellowish liquid: urine, the most accessible biological sample. Dipping their finger into the fluid and then licking it allowed...