Metabolism of Papaverine: IV. Urinary Elimination of Papaverine Metabolites in Man

Belpaire, F. M.; Rosseel, M. T.; Bogaert, M. G.

doi:10.3109/00498257809060953

Cited by 19 publications

(10 citation statements)

References 3 publications

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“…20 Two other poppy alkaloids, noscapine and papaverine, are extensively metabolized in humans, with less than 1% of the unchanged drug excreted in the urine. 22,23 Despite the ability of the UDAS method to detect these alkaloids (Table 1), neither were detected in urine of the study population; however, there was evidence for the presence of metabolites of both of these compounds. Meconine and desmethylmeconine are urinary metabolites of noscapine, and have been reported to account for approximately 2± 3% and 7± 75%, respectively, of an oral dose of the drug.…”

Section: Discussionmentioning

confidence: 92%

Diamorphine treatment for opiate dependence: putative markers of concomitant heroin misuse

2001

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The supply of substitute opioid medication as a treatment for heroin dependence is now common practice. There is growing international interest in the prescription of injectable diamorphine for subgroups of patients who are unable to stop injecting opiate drugs; in the United Kingdom it is estimated that there are currently 300 patients prescribed diamorphine for this purpose. The detection of illicit heroin misuse (through urinary diamorphine metabolites) is confounded in subjects prescribed diamorphine. We investigated the potential to distinguish between the use of street heroin and pharmaceutical diamorphine through the detection in urine of various opiate alkaloids originating in the opium poppy, Papaver somniferum. Over a 7-week period, 532 clients of an urban substance misuse service provided a total of 1122 urine samples for clinical purposes. Using a novel mixed-mode solid-phase extraction and gas chromatography/mass spectrometry technique, we screened samples for morphine, 6-monoacetylmorphine, codeine, meconine, papaverine, noscapine, thebaine and their metabolites. All urine samples from diamorphine-treated patients were positive for morphine. Of samples from patients receiving other treatments, 30% (95%CI: 27-33%) were positive for morphine, indicating probable street heroin misuse. Of morphine-positive samples, 61% (95%CI: 55-67%), from the "other treatments" group were positive for at least one of codeine, meconine and putative noscapine or papaverine metabolites. This was reduced to 56% (95%CI: 50-62%) when excluding codeine. Only one sample (0.1%) was positive for any one of these putative markers in the absence of morphine, when excluding codeine. These findings show that the detection of urinary noscapine and papaverine metabolites is useful in distinguishing between use of pharmaceutical diamorphine and street heroin. This may be of benefit to promote safer and more effective prescribing of diamorphine in opiate dependency, and as an outcome measure in trials of diamorphine prescribing.

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Section: Discussionmentioning

confidence: 92%

Diamorphine treatment for opiate dependence: putative markers of concomitant heroin misuse

2001

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“…These observations are consistent with rapid in vivo clearance of [ 11 C]papaverine from PDE-10 enriched areas of the CNS in rats. Our imaging data may indicate that the 30 nM binding affinity of papaverine, when coupled with a reduced input function due to rapid clearance of papaverine from the blood result in CNS binding kinetics which are unsuitable for a radiotracer [10, 17]. Although clinical PET imaging studies with Carbon-11 tracers seldom require prolonged retention in target-areas, the radioactivity uptake ratios of [ 11 C]papaverine in both caudate and putamen to cerebellum at the time of transient equilibrium (10 min post injection) was close to unity, as can be inferred from the data shown in Figure 3.…”

Section: Resultsmentioning

confidence: 99%

Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation

Xu¹,

Jones²,

Li³

et al. 2010

Nuclear Medicine and Biology

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Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase 10A (PDE10A) with IC 50 values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiological role of PDE10A. Here, we report the radiosynthesis of [ 11 C]papaverine and the in vitro and in vivo evaluation of [ 11 C]papaverine as a potential PET radiotracer for imaging PDE10A in the CNS. The radiosynthesis of papaverine with 11 C was achieved by O-methylation of the corresponding desmethyl precursor with [ 11 C]methyl iodide. [ 11 C]papaverine was obtained with ~70% radiochemical yield and a specific activity > 10 Ci/μmol (EOB). In vitro autoradiography studies of rat and monkey brain sections revealed selective binding of [ 11 C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [ 11 C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. microPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [ 11 C]papaverine from brain. Our initial evaluation suggests that despites papaverine's utility for in vitro studies and as a pharmaceutical tool, [ 11 C]papaverine is not an ideal radioligand for clinical imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.

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“…Moreover, a comparison with previously published studies concerning alkaloid concentrations of poppy seed products revealed fluctuating morphine concentrations within the same product. Due to an extensive metabolism of noscapine and papaverine in human body, coupled with a short half-life of papaverine (0.8-1.5 h), [17][18][19] urinary detection after poppy seed ingestion is rather unlikely. In contrast, in this study a morphine concentration of merely 0.649 μg/g could be confirmed.…”

Section: Discussionmentioning

confidence: 99%

“…[12,15,16] Similar to the results published by Trafkowski et al, [16] neither noscapine nor papaverine were detectable in urine samples after consumption of poppy seeds containing up to 37 μg noscapine and up to 9.8 μg papaverine. Due to an extensive metabolism of noscapine and papaverine in human body, coupled with a short half-life of papaverine (0.8-1.5 h), [17][18][19] urinary detection after poppy seed ingestion is rather unlikely. Though, proof of these natural occurring poppy seed alkaloids in urine following consumption of poppy seed products with particularly high levels of these alkaloids cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Urinary excretion study following consumption of various poppy seed products and investigation of the new potential street heroin marker ATM4G

Maas

Krämer

Sydow

et al. 2016

Drug Testing and Analysis

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Discrimination between street heroin consumption and poppy seed ingestion represents a major toxicological challenge in daily routine work. Several difficulties associated with conventional street heroin markers originate from their versatile occurrence in various poppy seed products and medications, respectively, as well as to small windows of detection. A novel opportunity to overcome these hindrances is represented by the new potential street heroin marker acetylated-thebaine-4-metabolite glucuronide (ATM4G), originating from thebaine during street heroin synthesis followed by metabolic reactions after administration. In this study, urine samples after consumption of different German poppy seed products and urine samples from subjects with suspicion of preceding heroin consumption were tested for ATM4G, 6-AC (6-acetylcodeine), papaverine, noscapine, 6-MAM (6-monoacetylmorphine), morphine, and codeine. Neither 6-AC and 6-MAM nor ATM4G but morphine and codeine could be detected in urine samples following poppy seed ingestion. As well, neither papaverine nor noscapine could be observed even after consumption of poppy seeds containing up to 37 µg noscapine and up to 9.8 µg papaverine, respectively. Concerning the urine samples with suspicion of preceding heroin consumption, ATM4G could be detected in 9 of 43 cases. By contrast, evidence of 6-AC and 6-MAM, respectively, could only be seen in 7 urine samples. In conclusion, ATM4G should be measured additionally in cases requiring discrimination of street heroin consumption from poppy seed intake. Copyright © 2016 John Wiley & Sons, Ltd.

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Metabolism of Papaverine: IV. Urinary Elimination of Papaverine Metabolites in Man

Cited by 19 publications

References 3 publications

Diamorphine treatment for opiate dependence: putative markers of concomitant heroin misuse

Diamorphine treatment for opiate dependence: putative markers of concomitant heroin misuse

Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation

Urinary excretion study following consumption of various poppy seed products and investigation of the new potential street heroin marker ATM4G

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