Publications (6)10.11 Total impact
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Article: Evaluating the relationship of methadone concentrations and EDDP formation in chronic pain patients.
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ABSTRACT: Methadone is used to treat moderate to severe pain in patients not responsive to non-narcotic analgesics and for maintenance treatment of opioid addiction. Methadone is primarily metabolized by N-demethylation to an inactive metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) by CYP3A4 and CYP2B6. Establishing expected concentrations for metabolism of methadone to EDDP using urine excretion data may be useful for monitoring "medications" and toxicity. Urine specimens from chronic pain patients were collected during routine clinic visits. Methadone and EDDP were quantified by liquid chromatography-tandem mass spectrometry. Approximately 8,000 subjects who reported taking methadone had creatinine concentrations ≥20 mg/dL, and excreted concentrations of methadone and EDDP above ≥100 ng/mL were selected. The median methadone urine concentration was 3.03 mg/g cr. Ninety-five percent of the population had concentrations between 0.175 and 20.9 mg/g cr. EDDP was, on average, twice the methadone concentration. The wide variance in relationship of methadone to its metabolite was not concentration-dependent. Variability between subjects was larger than variability within subjects. As the urinary pH increased, the proportion of excreted EDDP increased, implying a preferred excretion of EDDP.Journal of analytical toxicology 05/2012; 36(4):239-49. · 2.02 Impact Factor -
Article: Observations on the metabolism of morphine to hydromorphone in pain patients.
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ABSTRACT: Morphine is one of several opioids used to treat chronic pain. Because of its high abuse potential, urine drug tests can confirm "consistency with prescribed medications." Hydromorphone is a recently described minor metabolite of morphine, but few data exist on the characteristics of this metabolic pathway or the relationship of morphine and hydromorphone between and within subjects. Part I of this retrospective study shows that formation of hydromorphone from morphine is concentration-dependent and possibly saturated at high concentrations of morphine. In addition, the percentage of ultra-rapid metabolizers and poor metabolizers can be determined using the lower asymptote of a sigmoidal mathematical fit and are estimated to be 0.63 and 4.0%, respectively. Expected limits of morphine and hydromorphone (as a result of morphine metabolism) concentrations in the urine were established. Part II of this study used the metabolic ratio (hydromorphone-morphine) to determine the inter-patient and intra-patient variability in morphine metabolism to hydromorphone. Metabolic ratio values varied over a large range; 25-fold and 7-fold, respectively. The expected limits established in this study can assist in assessing the cause for possible variances in metabolism, such as drug interactions. The wide variability between and within subjects may explain unpredictable, adverse effects.Journal of analytical toxicology 05/2012; 36(4):250-6. · 2.02 Impact Factor -
Article: Observations on the urine metabolic ratio of oxymorphone to oxycodone in pain patients.
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ABSTRACT: The object of this study was to evaluate the metabolism of oxycodone to oxymorphone in a pain patient population using a quantitative liquid chromatography-tandem mass spectrometry analysis of 32,656 urine specimens obtained from pain patients between March 2008 and Feb 2010. The observed excretion was modeled using logarithmic transformation and approximated a Gaussian distribution. Oxycodone excretion into urine had a geometric mean of 1.93 mg/g of creatinine and oxymorphone had a value of 0.41 mg/g of creatinine. Increasing concentrations of oxycodone correlated with a smaller proportion of oxymorphone excretion suggesting saturation of oxycodone metabolism. Urine samples containing oxycodone without oxymorphone allowed an estimation of the proportion of poor metabolizers (2.4 ± 2.1%) in the population. A similar analysis of samples containing oxymorphone without oxycodone gave an estimate of the proportion of ultra-rapid metabolizers (1.8 ± 1.1%) in the population. Samples with concentrations of oxycodone above 10 mg/g of creatinine showed a sub-population of subjects with metabolic ratios roughly 100-fold less than the linear predictive model in this study. This study describes typical ranges for oxycodone and oxymorphone in urine, and showed that it is possible to identify fast or slow metabolizers who may be at risk for adverse events.Journal of analytical toxicology 05/2012; 36(4):232-8. · 2.02 Impact Factor -
Article: Evaluating the relationship between carisoprodol concentrations and meprobamate formation and inter-subject and intra-subject variability in urinary excretion data of pain patients.
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ABSTRACT: Using urinary carisoprodol data from pain patients, our objectives were to determine the relationship between carisoprodol concentration and its conversion to meprobamate, and quantify the intra-subject and inter-subject variability in carisoprodol metabolism. Liquid chromatography-tandem mass spectrometry was used to quantitate carisoprodol and meprobamate concentrations in urine specimens. The log creatinine-corrected carisoprodol versus log creatinine-corrected meprobamate showed a marginal positive relationship (R(2) = 0.395), with a 29.1-fold variance between subjects at the mean carisoprodol concentration. The geometric mean carisoprodol and meprobamate urine concentrations were 0.519 ± 3.38 mg and 28.2 ± 2.34 mg analyte per gram creatinine, respectively. The log metabolic ratio (MR) versus log creatinine-corrected carisoprodol displayed a marginal positive correlation. A subpopulation of outliers with higher carisoprodol and lower meprobamate levels were considered poor metabolizers and represented 0.483% (n = 21) of the study population. Using a curve-fit mathematical model, we estimated 0.318% (n = 10) to be ultra-rapid metabolizers. The inter-subject population geometric standard deviation (SD) of the MR was 3.64. The intra-subject geometric median and mean SD of the MR were 1.60 (interquartile range: 1.28, 2.07) and 1.72 ± 1.60, respectively. Inter-subject variability was 2.27 times greater than the median intra-subject variability. With a better understanding of urine carisoprodol and meprobamate concentrations and variability, urine drug testing provides a useful monitoring reference for clinicians.Journal of analytical toxicology 05/2012; 36(4):221-31. · 2.02 Impact Factor -
Article: Relationship between the concentration of hydrocodone and its conversion to hydromorphone in chronic pain patients using urinary excretion data.
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ABSTRACT: Hydrocodone in combination with acetaminophen is commonly used to control moderate pain and is metabolized by cytochrome P4502D6 to form the active metabolite, hydromorphone. The purpose of this study was to determine the metabolic relationship and variability between hydrocodone and its conversion to hydromorphone using urinary excretion data from chronic pain patients. Liquid chromatography-tandem mass spectrometry was used to quantitate hydrocodone and hydromorphone concentrations in urine specimens. The first visits of 25,200 subjects who took hydrocodone and not hydromorphone and had measurable concentrations were included in this study. The geometric mean (95% confidence index) of hydrocodone and hydromorphone urine concentrations were 1.39 (1.37-1.41) mg per gram of creatinine and 0.224 (0.221-0.227) mg per gram of creatinine, respectively. The log of creatinine-corrected hydromorphone versus the log of creatinine-corrected hydrocodone showed a positive relationship (R(2) = 0.20), with 60-fold variability between subjects. The plot of the log of the metabolic ratio ([hydromorphone] divided by [hydrocodone]) versus the log of creatinine-corrected hydrocodone had a coefficient of determination of R(2) = 0.42, with 125-fold variability between subjects. Ultra-rapid metabolizers represented 0.6% of the population, whereas 4% were poor metabolizers. Within-subject variability for the excretion of hydrocodone in urine was 23-fold, whereas between-subject variability was 134-fold. Hydrocodone and hydromorphone urine concentrations showed great variability within and between subjects.Journal of analytical toxicology 05/2012; 36(4):257-64. · 2.02 Impact Factor -
Article: Variability of transdermal fentanyl metabolism and excretion in pain patients.
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ABSTRACT: The rising popularity of the fentanyl transdermal patch and the striking number of deaths attributed to its prescribed use have brought attention to the large variability of fentanyl metabolism and the need for predictive models to prevent toxicity. The purpose of this study was to determine the amount of both intrasubject and intersubject variability in fentanyl metabolism and excretion, using urinary excretion data from patients with chronic pain prescribed the fentanyl transdermal patch. Liquid chromatography tandem mass spectrometry analytical technique was used to quantitate fentanyl and norfentanyl concentrations in spot urine specimens, after incubation with glucuronidase. Descriptive statistics and graphical analysis were conducted using Microsoft Excel 2007. Analysis was conducted on 206 subjects with > or = 2 visits listing transdermal fentanyl as current medication. Outliers and subjects with no detectable levels of drug were excluded, resulting in subject populations of 200 (all subjects analyzed) and 166 (subjects with drug concentrations above the instrument detection limit for all visits). The geometric mean metabolic ratio (MR) of norfentanyl to fentanyl was 6.2 x division by 2.4. A wide distribution was observed in total fentanyl load (1,000-fold) and MR (200-fold). The intersubject geometric standard deviation in MR was 2.4 (95% confidence interval [CI] for MR: 1-37) and the intrasubject geometric standard deviation was 1.8 (95% CI for MR: 2-20). The level of intrasubject variability over time in the pharmacokinetics of the fentanyl patch is much greater than previously observed and may be due to variability in absorption, interference of metabolism by concomitant medications, and variable metabolism due to genetic polymorphisms. The variation in the MR between subjects and within subjects may explain the unpredictable adverse effects observed with use of transdermal fentanyl.Journal of opioid management 6(1):29-39.
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2012
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University of California, San Diego
San Diego, CA, USA -
CSU Mentor
Long Beach, CA, USA
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