Biomedical subjects

Steven H Wong

Publications and source records attributed to Steven H Wong.

5 recordsLinked to original sources

PubMed2006

Negative urine opioid screening caused by rifampin-mediated induction of oxycodone hepatic metabolism.

INTRODUCTION: Oxycodone has become widely used in the clinic for the treatment of chronic pain. This reflects its favorable pharmacokinetics and side effect profiles. CASE REPORT: We report a 60-y-old man who had a clinically significant drug interaction between rifampin and oxycodone, resulting in 3 consecutive negative urine oxycodone screens in a 2-month period, suggesting non-adherence. A combination of urine opioid metabolite quantification by GC/MS and CYP genotyping confirmed that he was compliant with his oxycodone therapy. Determination of the complete oxycodone metabolite profile and the CYP3A4/5 and 2D6 genotype allowed the physician to be confident that the patient was compliant with the medication (and not diverting it) and to increase his oxycodone dose to optimize his pain control. CONCLUSION: This case demonstrates how the combination of analytical toxicology and pharmacogenetic analyses enhances a physician's ability to personalize drug therapy in patients with chronic pain syndromes.

Cytochrome P-450 CYP2D6↗

PubMed2005

Pharmacogenomics as molecular autopsy for forensic toxicology: genotyping cytochrome P450 3A41B and 3A53 for 25 fentanyl cases.

Pharmacogenomics, the study on genetic contributions to drug action may help in certifying fentanyl toxicity. Fentanyl is used clinically as an adjunct to surgical anesthesia and for chronic pain management. Its toxicity may be partially due to cytochrome P450 (CYP) 3A4*1B and 3A5*3 variant alleles, resulting in variable fentanyl metabolism. In this study, we examined 25 fentanyl-related deaths (22 Caucasians, 1 African-American, and 2 Native-Americans) from the Milwaukee County Medical Examiner's Office and referral cases. Fentanyl and norfentanyl in postmortem blood samples were analyzed by radioimmunoassay and liquid chromatography-mass spectrometry-mass spectrometry. The samples were then genotyped for CYP3A4*1B and 3A5*3 using Pyrosequencing. Genotyping showed: 1 CYP3A4*1B homozygous and CYP3A5*3 heterozygous, 1 compound CYP3A4*1B and CYP3A5*3 heterozygous, 22 CYP3A4*1B wild type and CYP3A5*3 homozygous, and 1 CYP3A5*3 and CYP3A4*1B wild type. CYP variant allelic frequencies of the 25 cases were 6% for CYP3A4*1B and 92% for CYP3A5*3, compared with normal Caucasian CYP3A4*1B, 3-8%, and CYP3A5*3, 85-95%. The mean fentanyl concentration and metabolic ratio of fentanyl to norfentanyl of the 2 cases with CYP3A4*1B and CYP3A5*3 variants were 12.8 and 1.4 microg/L, respectively, lower than those of 22 cases with wild type CYP3A4*1B and CYP3A5*3 homozygous variants, 16.7 and 7.3 microg/L, respectively. The postmortem/in vivo data provided the first scientific evidence that CYP3A5 is involved in the fentanyl metabolism, and homozygous CYP3A5 *3 causes impaired metabolism of fentanyl, and genotyping CYP3A4*1B and 3A5*3 variants may help to certify the fentanyl toxicity.

Adult↗

PubMed2004

Pharmacogenomic genotyping methodologies.

"Personalized medicine" based on an individual's genetic makeup is slowly becoming a reality as pharmacogenomics moves from the research setting to the clinical laboratory. Concordance studies between genotype and phenotype have shown that inherited mutations in several key drug-metabolizing enzymes, such as cytochrome P450 ( CYP ) 2D6 , 2C9 , and 2C19 , result in several distinct phenotypes that lead to different individual responses following drug administration. One of the major driving forces behind pharmacogenomics and its ability to be used effectively are the technologies that are available. A beneficial genotyping test must identify most or all of the mutations that have a significant impact on the expression or function of drug-metabolizing enzymes, transporter proteins, and/or drug receptors. Selection of the appropriate technology will be based on several issues, including prior knowledge of the mutation/polymorphism, sensitivity/specificity, sample requirements, and cost. Since the future volume of pharmacogenomic testing is anticipated to be large, automation of pharmacogenomics will also become increasingly important. This paper provides an overview of current technologies available for assessing polymorphisms on a small- to large-scale basis.

Alleles↗

PubMed2003

Pharmacogenomics as an aspect of molecular autopsy for forensic pathology/toxicology: does genotyping CYP 2D6 serve as an adjunct for certifying methadone toxicity?

Pharmacogenomics, applied as an aspect of molecular autopsy, may be used as an adjunct for certifying methadone fatalities. Methadone is metabolized by cytochrome P-450 (CYP) 1A2, 3A4, and 2D6. We hypothesized that methadone toxicity may be partially due to CYP 2D6 *3, *4, and *5 variant alleles, resulting in poor drug metabolism. A retrospective analysis was performed on covariables and risk factors of 21 methadone cases from the Milwaukee County Medical Examiner's Office (1998-2000). PCR genotyping showed: one heterozygous for 2D6*3, two homozygous for 2D6*4, five heterozygous for 2D6*4, and one heterozygous for both 2D6*3 and *4. This limited number of cases showed that the prevalence of poor metabolizer was higher but not significantly different from that of a control group (n = 23) (P > 0.05, Fisher Exact Test). Thus, CYP 2D6 mutations may not yet be directly associated with methadone toxicity. However, pharmacogenomics, complementing other case findings, served as an adjunct in interpreting methadone toxicity of poor and intermediate metabolizers.

Adult↗

PubMed2002

Pharmacogenomics as molecular autopsy for postmortem forensic toxicology: genotyping cytochrome P450 2D6 for oxycodone cases.

Pharmacogenomics, the study of the impact of heritable traits on pharmacology and toxicology, may serve as an adjunct for certifying opioid fatalities. Oxycodone, frequently prescribed for the relief of moderate to severe pain, is metabolized by cytochrome P450 (CYP) 2D6, encoded by a polymorphic gene with three mutations (*3, *4, and *5) with a combined 95% allelic frequency and about 10% prevalence. Individuals with variant alleles are more susceptible to oxycodone toxicity. By assessing the prevalence of CYP2D6 polymorphisms and covariables, we hypothesized that oxycodone fatality may be partially due to poor drug metabolism caused by CYP2D6 variant alleles. From the Milwaukee County Medical Examiner's Office (MCMEO), a retrospective analysis of 15 oxycodone cases was followed by genotyping blood samples for the variant alleles by conventional and real-time PCRs. Institutional Review Board approval was obtained. Oxycodone, extracted from blood and/or urine, was quantitated by GC-MS. The results show two homozygous for 2D6*4 and four heterozygous for 2D6*4. The MCMEO was not significantly different from those in the control group (n = 26) (p > 0.05, Fisher's Exact Test). However, genotyping CYP2D6 provided a more definitive interpretation of the oxycodone toxicity in four cases. Therefore, pharmacogenomics may serve as an adjunct in the determination of the cause and manner of death in forensic toxicology and a pharmacogenomic algorithm for genotyping has been proposed.

Adolescent↗