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Record number of fake drugs are seized in crackdown

BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f4204 (Published 28 June 2013) Cite this as: BMJ 2013;346:f4204

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The record number of fake drugs seized under Operation Pangea VI is just the tip of the iceberg. At present, we don’t really know the size of the European market for illicit medicines, neither do we know much about public exposure, let alone the incurred health damage. We therefore set out to estimate the actual use of illicit medicines by using sewage epidemiology. Sewage epidemiology is an established science for monitoring drugs of abuse.[1] It involves the back calculation of drugs and their metabolites in sewage to their corresponding original intake. When applying this methodology to illegal medicines the major difference is having to account for the fraction of legitimately dispensed medication. We selected sildenafil (Viagra®, Revatio®) as a model compound as it is the most prevalent drug in seized illicit medicines.[2] At the time of this study, generic sildenafil was not legally available.

To estimate the legitimate use of sildenafil we used the Dutch national dispensary database that covers 97% of all legitimate sales. For each patient in the sampled areas, the milligrams of sildenafil purchased were divided by the number of days until the next purchase. When a patient would not return after a purchase his own average consumption was used for his last purchase. When a patient would not return after a first purchase, the city populations’ average consumption was assumed. The individual data were summed to provide the average daily consumption from 12 months prior to the study until 3 months after. Because Viagra® is taken as needed, and mostly around the weekend, we used a 7-day average consumption for the sampling week (Wednesday – Tuesday). Revatio® is used daily and accounts for about 25% of the legitimate sildenafil consumption. The use of sildenafil in hospitals was ignored as it was negligible.

Sewage sampling was performed at the sewage treatment plants (STPs) for Amsterdam (769.000 inh.), Eindhoven (450.300 inh.) and Utrecht (300.000 inh.). Flow proportional samples were taken about every 10 minutes and were analysed as 24h-average samples. Sampling started on a Wednesday to catch the expected peak levels for sildenafil at the weekend. The STPs for Amsterdam and Utrecht serve most of the cities whereas the STP for Eindhoven serves the city as well as its surrounding communities. It takes excreta several hours to reach the sewage treatment plant depending on the sewage system (Amsterdam (±12h), Eindhoven (±3h), and Utrecht (±6h)). Sildenafil and its metabolites UK-103,320 and UK-150,564 were identified and quantified in all 21 samples.

To estimate the actual use of sildenafil, sewage loads were back calculated according to literature data.[3] This shows that in fasted men, about 92% of oral sildenafil is absorbed after which it is prone to rapid metabolism. About 25% of the original dose (equivalent to 27% of the absorbed dose) is excreted as UK-103,320 and UK-150,564. Although this study does not report the excretion of unchanged sildenafil, it is reported in the sewage of several cities.[4, 5] As stable ratios of the three analytes ruled out significant dumping of unused medication we concluded that, in the general population, sildenafil is excreted unchanged indeed. Thus, the actual sildenafil consumption was estimated by summing the sewage load of unchanged sildenafil and the absorbed dose. The absorbed dose was back calculated from the metabolite load using the formula: [(Load UK-103,320 (moles) + Load UK-150,564 (moles)) / 0,27]*474. For a conservative estimate, we assumed there were no losses of compounds in sewage due to degradation. The unchanged sildenafil in Amsterdam, Eindhoven and Utrecht respectively accounted for 10%, 9% and 10% of the estimated actual consumption, matching the oral absorbance reported in literature.

It is our conservative estimate that a considerable fraction of the sewage loads cannot be explained by legitimately prescribed sildenafil: Amsterdam (61%), Eindhoven (79%), and Utrecht (66%). Tourism appears to play a limited role as Amsterdam proportionally receives most tourists, yet has the lowest unexplained fraction. Commuting may have some influence as Eindhoven has the highest unexplained fraction and its STP also serves the surrounding communities where most of its commuters live. Nevertheless, the unexplained fraction of sildenafil is primarily ascribed to the use of illicit sildenafil.[6] If this is representative of other communities, the consumption of illicit erectile dysfunction drugs might dwarf the consumption of the legitimately dispensed versions. Therefore, the apparent success of rogue online pharmacies would be an important area of further inquiry.

References
1. Castiglioni S, Bijlsma L, Covaci A, et al. Evaluation of uncertainties associated with the determination of community drug use through the measurement of sewage drug biomarkers. Environ Sci Technol 2013; 47(3): 1452-60.
2. Venhuis BJ, de Kaste D. Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: A history, analytical aspects and health risks. J Pharm Biom Anal 2012; 69; 196-208.
3. Muirhead GJ, Rance DJ, Walker DK, et al. Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil citrate. Br J Clin Pharmacol 2002; 53(S1): 13S-20S.
4. Nieto A, Peschka M, Borrull F, et al. Phosphodiesterase type V inhibitors: Occurrence and fate in wastewater and sewage sludge. Water Res 2010; 44(5): 1607-15.
5. Schroder HF, Gebhardt W, Thevis M. Anabolic, doping, and lifestyle drugs, and selected metabolites in wastewater--detection, quantification, and behaviour monitored by high-resolution MS and MS(n) before and after sewage treatment. Anal Bioanal Chem 2010; 398(3): 1207-29.
6. To check the methodology it was also applied to methylphenidate (e.g. Ritalin®). We did not expect to find an illicit fraction as illicit methylphenidate is rarely seized. This was confirmed based on the ritalinic acid levels in sewage and the estimated consumption from dispension records.

Competing interests: No competing interests

02 July 2014
Bastiaan J. Venhuis
Senior Scientific Officer
Pim de Voogt, Erik Emke, Ana Causanilles, Peter Keizers
National Institute for Public Health and the Environment RIVM
Anthonie van Leeuwenhoeklaan 9, 3721MA