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 153
- Downloads 0
Mercury Exposure Through Gold Extraction: Varied Signs and Symptoms of Toxicity
A 48-year-old male called the poison control center noting his “skin is starting to peel off”. He stated ten days prior, a container fell from a shelf and spilled approximately 100 milliliters of elemental mercury used f...
Dose-Dependent Hematological, Hepatic and Gonadal Toxicity of Cypermethrin in Wistar Rats
Background: Pesticides are used frequently and may have various adverse effects on human health in different ways. Cypermethrin (CYP) is a synthetic type II pyrethroid pesticide that has been used extensively to control...
Statistical Parameters of Forensic Importance for 15 Autosomal STRs in Mestizo Population from the State of Guerrero (South Mexico)
Background: Human identification requires the maintenance of population databases of short tandem repeat (STR) loci that allow for their correct interpretation during paternity testing and forensic cases. Material and Me...
Environmental Toxicants in Forensic Entomology
The fundament of toxicology is the risk-benefit analysis. Certain chemical exists in the environment that if ingested, even in minute quantities, may alter bodily functions, induce death and interfere with the rate of de...
In Vitro Cytotoxicity and Antioxidative Potential of Nostoc Microscopicum (Nostocales, Cyanobacteria)
Many cyanobacterial species (cyanoprokaryotes, blue-green algae) are potent producers of various secondary metabolites with low molecular weight and diverse biological activities (antitumor, antimycotic, antiviral, antim...