Association of the OPRM1 variant rs1799971 (A118G) and clinical manifestations in tramadol poisoned patients: a cross-sectional study.

INTRODUCTION: The opioid receptor mu1 is a protein coding gene that can have different codes for a protein and may have variations (polymorphisms) affecting how opioids work. The aim of this study was to investigate the prevalence of the most common opioid receptor mu1 polymorphism (A118G) and any relationship between this polymorphism and features following tramadol overdose. MATERIALS AND METHODS: This was a cross-sectional study of patients admitted with tramadol poisoning to an Iranian hospital. These patients were not taking any other drugs or medications and had no history of seizures. RESULTS: The results showed that among the 83 patients included in the study, 57 (69 per cent) had the AA genotype, 25 (30 per cent) had the AG genotype, and one (1 per cent) had the GG genotype for the opioid receptor mu1 A118G polymorphism. Nausea and/or vomiting occurred in nine (11 per cent) patients and dizziness in 38 (46 per cent) patients. Serious adverse events included seizures in 51 (60 per cent) patients and respiratory failure requiring mechanical ventilation in 21 (25 per cent) patients. However, there was no significant association between the opioid receptor mu1 A118G polymorphism and these adverse events. DISCUSSION: In our study, the frequency of the A allele was greater than the G allele, and the AA genotype was more prevalent than AG. The GG genotype was the least common among the polymorphisms of opioid receptor mu1 rs1799971. There was no significant association between the opioid receptor mu1 A118G polymorphism and symptoms in tramadol-poisoned patients. Although these allele proportions are similar to the results reported in other Caucasian populations, they are dissimilar to the findings in Chinese and Singaporean populations. In these Asian studies, the predominant allele was the G allele. It has been suggested that a mutated G allele will decrease the production of opioid receptor mu1-related messenger ribonucleic acid and related proteins, leading to fewer mu-opioid receptors in the brain. CONCLUSIONS: This study found no significant association between the opioid receptor mu1 A118G polymorphism and adverse outcomes in tramadol-poisoned patients. However, more research is needed to draw more definitive conclusions due to the limited evidence and variability of opioid receptor mu1 polymorphisms in different populations.

Genetic variants associated with ALT elevation from therapeutic acetaminophen.

BACKGROUND: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined. METHODS: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome. RESULTS: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort. CONCLUSION: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury.

Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.

Fentanyl overdoses and pharmacogenetics.

Fentanyl has been implicated as a major contributor to the increased number of opioid overdose deaths. Surprisingly, little is known about the pharmacogenetic influences on fentanyl pharmacokinetics or pharmacodynamics. Pharmacogenetic studies of fentanyl are based largely on small sample sizes and have examined the potential association of only a small number of high frequency variants in selected candidate genes primarily with postoperative pain. Few data are available on low frequency variants, variants from racially/ethnically diverse populations, or on other phenotypes. Given the genetic diversity of low frequency variants, DNA sequencing may be needed to determine whether pharmacogenetic differences may contribute to lethal opioid overdoses.

MicroRNA from a 12-h versus 20-h acetylcysteine infusion for paracetamol overdose.

Paracetamol overdose is common and microRNA (miR)-122 expression is increased with liver injury. We aimed to measure miR-122 in the setting of an abbreviated paracetamol overdose treatment regimen. We compared miRNA expression in patients treated for paracetamol poisoning with an abbreviated 12-h intravenous acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) or a 20-h regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) (NACSTOP trial). miR-122 expression is increased (decreased cycle threshold (Ct) values) with paracetamol liver injury. We assessed miR-122 expression in patients receiving the two acetylcysteine regimens and in a separate group with acute liver injury (ALI). We examined 121 blood samples in 38 patients. After 20 h of acetylcysteine, median alanine transaminase (ALT) was 12 U/L (18, 14) versus 16 U/L (11, 21) ( p = 0.17) and median miR-122 Ct was 30.1 (interquartile range (IQR): 28.9, 33.3) versus 31.4 (28.9, 33.9) ( p = 0.7) in the NACSTOP abbreviated and control groups, respectively. Median normalized miR-122 Ct after 20 h of acetylcysteine was 2.2 (IQR 1.9, 6.4), 1.1 (0.7, 2.9), 63.9 (2.5, 168), 123.2 (40.9, 207.8) in the NACSTOP-abbreviated, NACSTOP-control, ALI and hepatotoxicity groups, respectively. There was no significant difference in ALT or miRNA between NACSTOP treatment groups and no signal of increased liver injury from an abbreviated 12-h acetylcysteine regimen. These findings suggest that an abbreviated acetylcysteine regimen in low-risk patients who have overdosed on paracetamol is safe. Further study is required to validate this finding utilizing miRNA as a comparative biomarker.

Clinical consequences related to a defective elimination of clobazam caused by homozygous mutated CYP2C19 allele.

Introduction: Voluntary drug intoxication with benzodiazepines is common and in most cases without consequences. We report an interesting case of voluntary drug intoxication with clobazam (CLB) in a patient with a homozygous mutated CYP2C19 genotype. Case report: A 63-year-old Caucasian man was admitted to an intensive care unit for voluntary drug intoxication with CLB (1200 mg) complicated by prolonged hospitalization (46 days). The levels of CLB and N-desmethylclobazam (NCLB) in plasma were initially 8.3 and 14.8 mg/L. The persistence of a high concentration of NCLB (14.3 mg/L on day 30) suggested a lack of elimination. A homozygous mutated allele of CYP2C19*2 without enzyme activity was discovered. To overcome this phenotype, NCLB metabolism was induced by administering 100 mg of phenobarbital for 10 days, allowing patient improvement. Discussion: NCLB is the major active metabolite of CLB with a longer half-life and much higher steady-state plasma concentrations compared to the parent drug. The half-life elimination of CLB is 18 h that of NCLB is between 40 and 50 h. However, there is considerable inter-individual variation in the metabolism of CLB and of the report NCLB/CLB under the dependence of genotype of CYP2C19. These polymorphisms are not generally well-known by physicians and may lead to severe poisoning.

Prolonged QRS Widening After Aripiprazole Overdose.

BACKGROUND: Aripiprazole is an atypical antipsychotic with a long half-life. Overdose can result in protracted somnolence and cardiac disturbances, particularly QT interval prolongation. METHODS: This is a single case report of a 14-year-old boy who took an overdose of aripiprazole and developed QRS widening. CASE: A 14-year-old boy intentionally ingested 20 tablets of aripiprazole (5 mg). He was brought to the emergency department when his ingestion was discovered. The patient's vital signs were as follows: temperature, 37.7°C; heart rate, 108 beats/min; blood pressure, 138/98 mm Hg; and respirations, 16 breaths/min. Activated charcoal was administered within 90 minutes of ingestion. Initial electrocardiogram (EKG) showed sinus tachycardia, with a QRS of 138 ms and QT interval of 444 ms. QRS duration was 90 ms on an EKG performed 3 months earlier. A bolus of sodium bicarbonate was administered, and the patient was transferred to the pediatric intensive care unit. Repeat EKG demonstrated a QRS of 156 ms, and a sodium bicarbonate infusion was initiated. The patient continued to have QRS prolongation for the next 8 days, reaching a peak of 172 ms 3 days postingestion. Despite aggressive treatment with sodium bicarbonate, there was persistent QRS prolongation; however, the patient did not have any dysrhythmias and remained hemodynamically stable. The patient was discharged 9 days postingestion when the QRS duration normalized to 82 ms. Genetic testing revealed that the patient was a CYP2D6 poor metabolizer. CONCLUSIONS: This case suggests that aripiprazole toxicity may possibly be associated with QRS prolongation without associated dysrhythmias or cardiovascular compromise. In addition, toxicity may be prolonged in patients who are CYP2D6 poor metabolizers.

Plasminogen Activator Inhibitor-1 Reduces Tissue-Type Plasminogen Activator-Dependent Fibrinolysis and Intrahepatic Hemorrhage in Experimental Acetaminophen Overdose.

Acetaminophen (APAP)-induced liver injury in mice is associated with activation of the coagulation cascade and deposition of fibrin in liver. Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. PAI-1 expression is increased in both experimental APAP-induced liver injury and patients with acute liver failure. Prior studies have shown that PAI-1 prevents intrahepatic hemorrhage and mortality after APAP challenge, but the downstream mechanisms are not clear. We tested the hypothesis that PAI-1 limits liver-related morbidity after APAP challenge by reducing tPA-dependent fibrinolysis. Compared with APAP-challenged (300 mg/kg) wild-type mice, hepatic deposition of cross-linked fibrin was reduced, with intrahepatic congestion and hemorrhage increased in PAI-1-deficient mice 24 hours after APAP overdose. Administration of recombinant wild-type human PAI-1 reduced intrahepatic hemorrhage 24 hours after APAP challenge in PAI-1-/- mice, whereas a mutant PAI-1 lacking antiprotease function had no effect. Of interest, tPA deficiency alone did not affect APAP-induced liver damage. In contrast, fibrinolysis, intrahepatic congestion and hemorrhage, and mortality driven by PAI-1 deficiency were reduced in APAP-treated tPA-/-/PAI-1-/- double-knockout mice. The results identify PAI-1 as a critical regulator of intrahepatic fibrinolysis in experimental liver injury. Moreover, the results suggest that the balance between PAI-1 and tPA activity is an important determinant of liver pathology after APAP overdose.

Dihydrocodeine Overdoses in a Neonate and in a 14-year-old Girl Who Were Both Genotyped as Cytochrome P450 2D6*1/*10-*36: Comparing Developmental Ages and Drug Monitoring Data With the Results of Pharmacokinetic Modeling.

A high activity of cytochrome P450 2D6 (CYP2D6) reportedly leads to toxicity of dihydrocodeine/codeine by increasing toxic potential of their metabolite dihydromorphine/morphine, which are further metabolized to highly active dihydromorphine 6-O-glucuronide and the less active morphine 3-O-glucorinide but rapidly excreted into urine as water-soluble forms. A case of acute respiratory depression after administration of prescribed dihydrocodeine phosphate (2.0 mg/d divided twice a day for 2 days) to a 1-month-old baby boy genotyped as CYP2D6*1/*10-*36 is described. The case is compared with that of a 14-year-old girl, also genotyped as CYP2D6*1/*10-*36, presenting in an agitated state after an overdose (37 mg) of dihydrocodeine phosphate taken as simultaneous ingestion of multiple over-the-counter tablets. In contrast to the rapid clearance of dihydrocodeine from blood in the 14-year-old girl (apparent half-life of 3 hours), the 1-month-old baby boy still had high serum concentrations of dihydrocodeine (400 nmol/L) and dihydromorphine (1.9 nmol/L) 21 hours after the last oral administration of dihydrocodeine-containing cough mixture. The rapid clearance in the 14-year-old girl was mainly attributed to dihydrocodeine glucuronidation and partly attributed to dihydromorphine formation, as determined by liquid chromatography-tandem mass spectrometry analyses. However, the conjugation ratios of dihydrocodeine and dihydromorphine in the neonate were low in comparison with those in the 14-year-old girl and with those measured in 3-, 6-, and 13-year-old control subjects, resulting from the poorly developed glucuronidation potential of the neonate. The current observations suggest that the CYP2D6*1/*10-*36 genotype seen in the 2 Japanese patients may not significantly contribute to the likelihood of dihydrocodeine overdose but highlight the importance of considering age when prescribing dihydrocodeine.

Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity.

In the treatment of insulin-dependent diabetes the risk of a fatal insulin overdose is a persistent fear to most patients. In order to potentially reduce the risk of overdose, we report the design, synthesis, and biochemical characterization of a set of insulin analogs designed to be fractionally reduced in maximal agonism at the insulin receptor isoforms. These analogs consist of native insulin that is site-specifically conjugated to a peptide-based insulin receptor antagonist. The structural refinement of the antagonist once conjugated to insulin provided a set of partial agonists exhibiting between 25 and 70% of the maximal agonism of native insulin at the two insulin receptor isoforms, with only slight differences in inherent potency. These rationally-designed partial agonists provide an approach to interrogate whether control of maximal activity can provide glycemic control with reduced hypoglycemic risk.

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) HepaRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6-559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity.

MicroRNAs (miRNAs) that regulate the cytochrome P-450 isoforms involved in acetaminophen (APAP) toxicity were examined in HepaRG cells treated with APAP (20 mM). In-vitro studies found that APAP protein adducts were increased at 1 h, followed by ALT increases at 12 and 24 h. CYP1A2, CYP3A4 and CYP2E1 mRNA levels were decreased, while miRNAs were increased for miR-122-5p, miR-378a-5p, miR-27b-3p at 6 h and miR-125b-5p at 12 h and miR-27b-3p at 24 h. Putative miRNA binding sites on the 3'UTRs of the CYPs were identified in-silico. Overexpression of miR-122-5p and miR-378a-5p in cells suppressed protein expression of CYP1A2, CYP3A4 and CYP2E1. Luciferase reporter assays confirmed the interaction between miR-122 and the 3'UTR of the CYP1A2 and CYP3A4. Thus, the in-vitro experiments showed that miR-122-5p and miR-378a-5p upregulation were associated with translational repression of CYPs. Serum samples of children with APAP overdose had significant elevation of miR-122-5p, miR-378a-5p, miR-125b-5p and miR-27b-3p, compared to healthy controls and receiver operator curves of the miRNAs had AUCs of 91 to 100%. Collectively, the data suggest that miRNA elevations in APAP toxicity represent a regulatory response to modify CYP1A2, CYP3A4 and CYP2E1 translation due to cellular stress and injury.

Pramipexole Overdose Associated with Visual Hallucinations, Agitation and Myoclonus.

INTRODUCTION: Pramipexole is a dopamine D2 receptor agonist used to treat idiopathic Parkinson's disease and primary restless legs syndrome. There is limited information on pramipexole overdose. CASE REPORT: A 59-year-old male ingested 3 mg pramipexole, 2250 mg venlafaxine, 360 mg mirtazapine, with suicidal intent. He presented alert, had normal vital observations and normal pupillary reflexes. He was mildly agitated, reported visual hallucinations and was given 5 mg diazepam. He had a mildly elevated lactate of 1.7 mmol/L, but otherwise normal laboratory investigations. Overnight, he remained agitated with visual hallucinations and developed myoclonus while awake. He had increasing difficulty passing urine on a background of mild chronic urinary retention. On review, 14 h post-ingestion, he was hypervigilant, jittery and mildly agitated. He had pressured speech and difficulty focusing on questioning. He had a heart rate of 110 bpm, but had an otherwise normal examination, with no clonus or extrapyramidal effects. He was unable to mobilize due to dizziness and ataxia. Over the next few hours, he improved, the visual hallucinations and agitation resolved and he mobilized independently. Pramipexole was measured with liquid chromatography mass spectrometry. The initial plasma pramipexole concentration was 34.2 ng/mL (therapeutic range 0.2 to 7 ng/mL), 9 h post-overdose. Concentration time data fitted a one-compartment model with an estimated elimination half-life of 18 h. DISCUSSION: Pramipexole overdose with hallucination, agitation, and myoclonus is consistent with adverse effects reported with therapeutic toxicity, but mirtazapine and venlafaxine may have contributed. Pramipexole concentrations exceeded the therapeutic range for over 24 h. With the increasing use of pramipexole in restless legs syndrome, adult overdoses may become more common.

Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities.

Cytochrome P450 (CYP) enzyme 2B6 plays a significant role in the stereo-selective metabolism of (S)-methadone to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, an inactive methadone metabolite. Elevated (S)-methadone can cause cardiotoxicity by prolonging the QT interval of the heart's electrical cycle. Large inter-individual variability of methadone pharmacokinetics causes discordance in the relationship between dose, plasma concentrations and side effects. The purpose of this study was to determine if one or more single nucleotide polymorphisms (SNPs) located within the CYP2B6 gene contributes to a poor metabolizer phenotype for methadone in these fatal cases. The genetic analysis was conducted on 125 Caucasian methadone-only fatalities obtained from the West Virginia and Kentucky Offices of the Chief Medical Examiner. The frequency of eight exonic and intronic SNPs (rs2279344, rs3211371, rs3745274, rs4803419, rs8192709, rs8192719, rs12721655 and rs35979566) was determined. The frequencies of SNPs rs3745274 (*9, c516G > T, Q172H), and rs8192719 (21563 C > T) were enhanced in the methadone-only group. Higher blood methadone concentrations were observed in individuals who were genotyped homozygous for SNP rs3211371 (*5, c1459C > T, R487C). These results indicate that these three CYP2B6 SNPs are associated with methadone fatalities.

Blood gene expression profiling of an early acetaminophen response.

Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4 g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing, and 12 genes were detected with expression profiles significantly altered within 24 h. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure, and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.

Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues.

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as 'legal highs' in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many 'legal highs', little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.

The contribution of pharmacogenetics to pharmacovigilance.

Since the beginning of this century, information on pharmacogenetics appears in the summary of product characteristics (SPC) of drugs. Pharmacogenetic tests particularly concern the enzymes involved in the metabolism of drugs, among which P450 cytochromes. Some patients known as poor metabolisers eliminate some drugs more slowly, causing overdoses and adverse drug reactions (ADRs). The best-known examples are AVK and VKORC1-CYP2C9 or clopidogrel and CYP2C19. In the USA, the tests are recommended before the introduction of these drugs to prevent the occurrence of ADRs. Other tests are also commonly performed to address the toxicity of certain anticancer drugs (DPYD-capecitabine, UGT1A1-irinotecan, TPMT 6-mercaptopurine). Pharmacogenetic testing is also available to identify HLA loci that are very strongly associated with the occurrence of immuno-allergic reactions to a specific drug. The best-known example is HLA-B*5701, strongly associated with hypersensitivity to abacavir, and this test is now always prescribed before the instatement of this drug.

Differential Consequences of Tramadol in Overdosing: Dilemma of a Polymorphic Cytochrome P450 2D6-Mediated Substrate.

Tramadol is a centrally acting opioid analgesic that is prone to polymorphic metabolism via cytochrome P450 (CYP) 2D6. The generation of the active metabolite, O-desmethyltramadol, which occurs through the CYP 2D6 pathway, significantly contributes to the drug's activity. However, dosage adjustments of tramadol are typically not practiced in the clinic when treating patients who are homozygous extensive metabolizers, heterozygous extensive metabolizers, or poor metabolizers. In the event of a tramadol overdose, the consequences may be influenced importantly by the genotype or phenotype status of the subject. Depending on the individual subject's CYP 2D6 status, one may see excessive miotic-related toxicity driven by the excessive availability of O-desmethyltramadol or one may manifest mydriatic-related toxicity driven by the excessive availability of tramadol. This report provides pharmacokinetic perspectives in situations of tramadol overdosing.