Urinary metabolic ratio of pain management and substance abuse treatment drugs: Effect of age

We examined the effects of age on the metabolism of 18 drug pairs using urinary metabolic ratio (MR), defined as metabolite concentration/parent drug concentration. These drug pairs include dextrorphan/dextromethorphan, oxymorphone/oxycodone, hydromorphone/hydrocodone, O-desmethyltramadol/tramadol, hydromorphone/morphine, norbuprenorphine/buprenorphine, norfentanyl/fentanyl, noroxycodone/oxycodone, norhydrocodone/hydrocodone, 7-aminoclonazepam/clonazepam, α-hydroxyalprazolam/alprazolam, norquetiapine/quetiapine, meprobamate/carisoprodol, N-desmethyltapentadol/tapentadol, norketamine/ketamine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine/methadone, desipramine/imipramine, and nortriptyline/amitriptyline. MR data were log-transformed for analysis. This was a retrospective study that used specimens submitted for urine drug testing by patients on chronic pain medications and those undergoing substance abuse rehabilitation. We included patients who were 20 years old and older, and subdivided age groups in 10-year increments. Due to small sample sizes, meprobamate, tapentadol, and imipramine were subdivided into 20-year increments. Specimens were filtered for potential drug–drug interactions. Testing was performed with a clinically validated liquid chromatography–tandem mass spectrometry method on the Shimadzu LC-20 XR paired with a Sciex 6500+ mass spectrometer. Chromatographic separation was achieved with a methanol–formic acid–water gradient on a Kinetex phenyl-hexyl column. Results were analyzed using Indigo Bio Automation Ascent software with a four-point calibration curve. We used a two-sample t-test to assess statistically significant differences between subsequent age groups and the control age group of 20-29 or 20-39 (p-value < 0.05) and measured the effect size using Hedges' g. All data analyses were performed in RStudio using the R language. Our data showed that drug metabolism is altered by age, captured as changes in the urinary MRs with increasing age. Most drugs showed the expected pattern of alteration over age, ie, their MRs decreased with increasing age. These drugs were largely processed by cytochrome (CYP)3A4, including buprenorphine, fentanyl, alprazolam, quetiapine, ketamine, methadone, imipramine, and amitriptyline. The metabolism of carisoprodol, which is processed by CYP2C19, also decreased with increasing age. Findings suggest decreased metabolic capacity in the elderly, probably due to decreased activities of CYP3A4 and CYP2C19. The metabolism of other drugs, which includes dextromethorphan, oxycodone, hydrocodone, and tramadol, showed an unexpected increase in MRs in the older age group (70 years and beyond). These drugs are largely processed by CYP2D6. Findings suggest minimal effect of age on CYP2D6 activity, or that CYP2D6 activity is not impaired in the elderly. Selection bias may also play a role. While we observed a slight increase in the MRs of oxycodone (→noroxycodone) and hydrocodone (→norhydrocodone), the overall effect is decreasing metabolism in the older age group (60-70 years and beyond). Metabolism of clonazepam also showed an unexpected increase in MR in the elderly. The metabolism of morphine and tapentadol was not significantly affected by age. Although data showed considerable variation in the effects of age on drug metabolism, it is evident that metabolism of most drugs is impaired in the elderly. Thus, our studies show that unusual metabolism can be due to aging. Monitoring MRs can be useful to assess drug metabolism, which allows for proper dose selection and optimal drug therapy, especially in the elderly.