Serum dextromethorphan/dextrorphan metabolic ratio for CYP2D6 phenotyping in clinical practice

Abstract

SUMMARYWhat is known and Objective: Accurate prediction of actual CYP2D6 metabolic activity may prevent some adverse drug reactions and improve therapeutic response in patients receiving CYP2D6 substrates. Dextromethorphan-to-dextrorphan metabolic ratio (MR DEM WHAT IS KNOWN AND OBJECTIVECYP2D6 plays a pivotal role in the metabolism of many drugs. It is a highly polymorphic enzyme, and to date, more than 80 allelic variants alleles have been identified. 1 The variant alleles may encode proteins with normal (e.g. CYP2D6*2), decreased (e.g. CYP2D6*10) or no (e.g. CYP2D6*4) enzyme activity. As a consequence, there is a wide range of CYP2D6 metabolic activity shows wide inter-subject variability. The CYP2D6 metabolic phenotype can be classified into four groups -poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM). 2 Thus, the same dose of a drug extensively metabolized by CYP2D6 can result in a different clinical response in patients depending on the P450 phenotype. 2 Moreover, CYP2D6-drug interactions may also have clinical consequences. For example, after administration of paroxetine, a CYP2D6 inhibitor, to patients on tamoxifen, a decrease in plasma levels of the active metabolite of tamoxifen was detected. 3 This change may have serious consequences in breast cancer treatment with tamoxifen. CYP2D6 ultrarapid metabolizer phenotype may cause failure of pharmacotherapy because of the very low and thus ineffective drug plasma levels. 4 In antipsychotic treatment, an association has been observed between extrapyramidal adverse effects and the CYP2D6 genotype. 5 Therefore, for drugs with narrow therapeutic indices, it seems to be useful to assess CYP2D6 metabolic activity prior to or during therapy with CYP2D6 substrates and to adjust the individual dosage according to the patient's phenotype. Such personalized pharmacotherapy may prevent adverse effects and improve response. Specific substrates (markers) that are metabolized selectively by CYP2D6 are often used for the assessment of metabolic activity. The concentration of specific substrate and its metabolite in body fluids (a ratio of molar concentrations; metabolic ratio) serves as a measure of the individual CYP activity. Histograms of log-transformed metabolic ratios may show cut-off values of MR which distinguish EM from PM, UM or IM. Suitable substrates for CYP2D6 include debrisoquine, bufuralol, tramadol, dextromethorphan, metoprolol and sparteine. 2,6 Debrisoquine and sparteine are not currently available, and except for dextromethorphan, the other substrates are seldom administered. Dextromethorphan remains the most widely used probe for CYP2D6 metabolic activity

Evaluation of CYP2D6 phenotype in the Yoruba Nigerian population

“…The age range in this study was similar to previous studies investigating CYP2D6 phenotype [24, 30, 31]. The established tolerability profile of dextromethorphan was further demonstrated by the fact that only one (~1%) participant in our study had mild and transient drowsiness [24, 28, 31–33]. In CYP2D6 phenotyping, the requisite cutoff(s) may be obtained by subjecting data to a probit analysis, Receiver Operating Characteristics (ROC) or other similar statistical analysis [28, 33, 34].…”

“…Dextromethorphan and dextrorphan concentrations in plasma and urine were analysed using a previously reported methods by Zimova et al [27] and Jurica et al [28] with modifications. Dextromethorphan hydrobromide syrup (Tussipect R ), (Belgium) 1.5mg/mL was supplied, in part, free by Benjamin Michael Pharmacy, Lagos, Nigeria.…”

Addressing phenoconversion: the Achilles' heel of personalized medicine

“…In one study in healthy Caucasian subjects, the DMR from urine collected over the time interval 0-4 h after the dose correlated reasonably well with those determined from plasma concentrations obtained at 3 h [123]. More recently, it has been shown that the DMRs determined using 0-8 h urine collection or a serum sample at 3 h postdose also correlate well with each other [124]. There is also available a 13 C-dextromethorphan breath test.…”

Venlafaxine pharmacokinetics focused on drug metabolism and potential biomarkers

“…Currently, the accepted phenotyping procedure consists of the determination of metabolic ratios (proportion between the amounts of unchanged drug and metabolite mediated by a specific isoenzyme) in body fluids, usually plasma and urine, within a certain time following a single-dose administration of the probe drug. Obviously, these procedures require the availability of appropriate analytical methodologies, usually LC-MS/ MS techniques, able to quantify both compounds probe drug and metabolite [61,64,83,86,87].…”