Since salbutamol has become the drug du jour, probably the drug of the year (and 2018) as far as the Clinic is concerned, I think it warrants a separate thread. This one is for discussion of (among other topics):
1) research suggesting possible performance-enhancing effects of the drug;
2) the pharmacokinetics of salbutamol, an understanding of which is necessary, among other things, to evaluate the possibility that Froome’s level is consistent with the drug’s being administered through blood transfusion.
3) details of the WADA test, including what forms of salbutamol are quantitated, any corrections for urine specific gravity, and studies that provide the rationale for the currently allowed limits
4) Any future test results that Froome presents as evidence for his innocence
5) The results of other salbutamol cases, as they are relevant to Froome’s case
So basically just the science. General discussion of Froome, including implications of this AAF for his future as a rider as well as his legacy, reactions of other riders, his protestations of innocence, Sky's reaction, and so on, can continue in the thread for that purpose.
I will begin my reposting some links I posted in the Froome thread.
https://www.ncbi.nlm.nih.gov/pubmed/22388343
https://www.ncbi.nlm.nih.gov/pubmed/19927035
These two studies by the same group measured urinary levels of salbutamol four hours after inhaling 800 ug (which is the 12 hour limit set by WADA). In the first study, only 1/18 subjects exceeded the 1000 ng/ml. urinary limit, and not by much (1057). Eight of the subjects were described as elite athletes with ashthma, and had a mean urinary level of about 335 ng/ml. Moreover, if the urine concentration in that one high sample was corrected for specific gravity—i.e., dehydration makes the urine solutes more concentrated than normal—the salbutamol concentration dropped to 661. I don’t know whether in the WADA testing procedure, this correction is carried out or not, but regardless, I assume the 1000 ng/ml was found to be appropriate to however the urine is treated. I also need to point out I saw another study reporting that making the SG correction actually increased the effective concentration, so sometimes subjects being tested apparently have very dilute urine.
In the second study, the mean value of ten subjects was just 261 ng/ml. So clearly, at the maximum permitted doses, going over the urinary limit is not common. In contrast, in both these studies, subjects also took 8 mg (ten times the inhalation dose) orally. The mean urinary values were 2000-3000, though there was enormous individual variation, as indeed, is the case regardless of route of administration.
https://www.ncbi.nlm.nih.gov/pubmed/16541373
In this study, the authors administered 100 ug doses of salbutamol twice daily to ten subjects, and on the basis of the urinary levels, concluded that the WADA limit could be lowered to just 250 ng/ml. Someone here who takes salbumatol can comment on whether 200 ug/day is a reasonable dose, or whether the 800 – 1600 ug dose is really necessary.
Another study reported a false positive rate of 4% using 500 ng/ml as the limit, but the amount inhaled was not given in the abstract. Also, the amounts will vary depending on whether the free or conjugated forms of the drug are measured. I'm not clear yet on whether the WADA urinary limit refers to free salbutamol or total, which makes a substantial difference, and also whether, as I mentioned above, the urine is corrected to a typical value of specific gravity. But overall, I think we can conclude that a value of 2000 ng/ml, as reported for Froome, is far more likely to result from an oral dose than an inhaled one. From what I've seen so far, I'd be a little surprised if he could get a urinary level that high by inhaling within the WADA limit.
Another interesting aspect of this is that in theory, one can distinguish inhaled from oral salbutamol from the ratio of free to sulfated, but this is difficult, apparently because when one inhales, one may actually swallow some of the substance? Maybe an asthmatic can comment on this?
Edit: Here are links to most of the issues discussed in this thread,as of 12/28/17:
Pharmacokinetics of salbutamol
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1401185/pdf/brjclinpharm00122-0093.pdf
http://onlinelibrary.wiley.com/doi/10.1002/cpt1972136861/full
https://link.springer.com/article/10.1007/BF02456001
Studies measuring urine levels following inhaled and/or oral doses
http://sci-hub.la/10.1249/MSS.0b013e3181b2e87d
http://sci-hub.la/10.1097/JSM.0b013e31823513e1
http://sci-hub.la/10.1055/s-2005-865627
http://sci-hub.la/10.1002/dta.1568
http://sci-hub.la/10.1002/dta.367
http://sci-hub.la/10.1097/jsm.0000000000000072
http://sci-hub.tw/10.1097/JSM.0b013e3181705c8c
http://sci-hub.la/10.1002/dta.1828
Performance enhancing effects of salbutamol
https://www.ncbi.nlm.nih.gov/pubmed/26197029
https://www.ncbi.nlm.nih.gov/pubmed/25077918
https://www.ncbi.nlm.nih.gov/pubmed/23559124
https://www.ncbi.nlm.nih.gov/pubmed/22230921
https://www.ncbi.nlm.nih.gov/pubmed/17264145
https://www.ncbi.nlm.nih.gov/pubmed/16687481
https://www.ncbi.nlm.nih.gov/pubmed/16195983
https://www.ncbi.nlm.nih.gov/pubmed/16195982
https://www.ncbi.nlm.nih.gov/pubmed/15459835
https://www.ncbi.nlm.nih.gov/pubmed/11071049
https://www.ncbi.nlm.nih.gov/pubmed/10926623
https://www.ncbi.nlm.nih.gov/pubmed/10912897
https://www.ncbi.nlm.nih.gov/pubmed/9200320
https://www.ncbi.nlm.nih.gov/pubmed/8587482
https://www.ncbi.nlm.nih.gov/pubmed/3293733
Studies of tolerance to salbutamol
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1975.tb00557.x/pdf
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1974.tb00255.x/full
http://www.atsjournals.org/doi/abs/10.1164/arrd.1980.121.6.973
http://www.sciencedirect.com/science/article/pii/S0091674999701788
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1975.tb00557.x/pdf
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1974.tb00255.x/full
http://www.atsjournals.org/doi/abs/10.1164/arrd.1980.121.6.973
http://www.sciencedirect.com/science/article/pii/S0091674999701788
http://www.sciencedirect.com/science/article/pii/014067369392695P
http://erj.ersjournals.com/content/21/5/810.long
Studies of metabolic effects of salbutamol, including weight loss and muscle growth
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2439523/#bib104
http://dmd.aspetjournals.org/content/39/5/864.long
http://dmd.aspetjournals.org/content/35/10/1797.long
https://www.ncbi.nlm.nih.gov/pubmed/26239482
https://www.ncbi.nlm.nih.gov/pubmed/7916118
Studies of amount of salbutamol inhaled under various conditions
http://sci-hub.la/10.1016/j.pupt.2017.06.004
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1806-37132011000600008&lng=en&nrm=iso&tlng=en
Urine specific gravity levels in cyclists
http://sci-hub.la/10.1123/ijsnem.2015-0188
http://sci-hub.la/10.1519/JSC.0b013e318240f677
http://sci-hub.la/10.1111/sms.12343
http://sci-hub.la/10.1097/JSM.0b013e3181b47c93
http://sci-hub.la/10.1136/bjsm.2008.049551
http://sci-hub.la/10.1186/1550-2783-11-12
http://sci-hub.la/10.1258/smj.2011.011287
http://sci-hub.la/10.1080/15438627.2011.582827
http://sci-hub.la/10.4085/1062-6050-49.3.85
http://sci-hub.la/10.1007/s00421-011-2024-y
http://sci-hub.la/http://journals.humankinetics.com/doi/abs/10.1123/ijspp.2012-0369
Legal issues, including WADA protocols and cases of other athletes
http://sci-hub.tw/10.1002/dta.2184
http://sci-hub.la/10.1385/CRIAI:31:2:259
http://www.cyclingnews.com/news/innocently-guilty-the-petacchi-case/
http://autobus.cyclingnews.com/news.php?id=news/2007/aug07/aug06news2
http://autobus.cyclingnews.com/news.php?id=news/2007/jun07/jun13news2
http://autobus.cyclingnews.com/news/?id=2003/mar03/mar24news2
https://jurisprudence.tas-cas.org/Shared%20Documents/1362,%201393.pdf
http://www.tas-cas.org/fileadmin/user_upload/Award__FINAL_.pdf
https://www.wada-ama.org/sites/default/files/resources/files/wada-td2017dl-v2-en_0.pdf
1) research suggesting possible performance-enhancing effects of the drug;
2) the pharmacokinetics of salbutamol, an understanding of which is necessary, among other things, to evaluate the possibility that Froome’s level is consistent with the drug’s being administered through blood transfusion.
3) details of the WADA test, including what forms of salbutamol are quantitated, any corrections for urine specific gravity, and studies that provide the rationale for the currently allowed limits
4) Any future test results that Froome presents as evidence for his innocence
5) The results of other salbutamol cases, as they are relevant to Froome’s case
So basically just the science. General discussion of Froome, including implications of this AAF for his future as a rider as well as his legacy, reactions of other riders, his protestations of innocence, Sky's reaction, and so on, can continue in the thread for that purpose.
I will begin my reposting some links I posted in the Froome thread.
https://www.ncbi.nlm.nih.gov/pubmed/22388343
https://www.ncbi.nlm.nih.gov/pubmed/19927035
These two studies by the same group measured urinary levels of salbutamol four hours after inhaling 800 ug (which is the 12 hour limit set by WADA). In the first study, only 1/18 subjects exceeded the 1000 ng/ml. urinary limit, and not by much (1057). Eight of the subjects were described as elite athletes with ashthma, and had a mean urinary level of about 335 ng/ml. Moreover, if the urine concentration in that one high sample was corrected for specific gravity—i.e., dehydration makes the urine solutes more concentrated than normal—the salbutamol concentration dropped to 661. I don’t know whether in the WADA testing procedure, this correction is carried out or not, but regardless, I assume the 1000 ng/ml was found to be appropriate to however the urine is treated. I also need to point out I saw another study reporting that making the SG correction actually increased the effective concentration, so sometimes subjects being tested apparently have very dilute urine.
In the second study, the mean value of ten subjects was just 261 ng/ml. So clearly, at the maximum permitted doses, going over the urinary limit is not common. In contrast, in both these studies, subjects also took 8 mg (ten times the inhalation dose) orally. The mean urinary values were 2000-3000, though there was enormous individual variation, as indeed, is the case regardless of route of administration.
https://www.ncbi.nlm.nih.gov/pubmed/16541373
In this study, the authors administered 100 ug doses of salbutamol twice daily to ten subjects, and on the basis of the urinary levels, concluded that the WADA limit could be lowered to just 250 ng/ml. Someone here who takes salbumatol can comment on whether 200 ug/day is a reasonable dose, or whether the 800 – 1600 ug dose is really necessary.
Another study reported a false positive rate of 4% using 500 ng/ml as the limit, but the amount inhaled was not given in the abstract. Also, the amounts will vary depending on whether the free or conjugated forms of the drug are measured. I'm not clear yet on whether the WADA urinary limit refers to free salbutamol or total, which makes a substantial difference, and also whether, as I mentioned above, the urine is corrected to a typical value of specific gravity. But overall, I think we can conclude that a value of 2000 ng/ml, as reported for Froome, is far more likely to result from an oral dose than an inhaled one. From what I've seen so far, I'd be a little surprised if he could get a urinary level that high by inhaling within the WADA limit.
Another interesting aspect of this is that in theory, one can distinguish inhaled from oral salbutamol from the ratio of free to sulfated, but this is difficult, apparently because when one inhales, one may actually swallow some of the substance? Maybe an asthmatic can comment on this?
Edit: Here are links to most of the issues discussed in this thread,as of 12/28/17:
Pharmacokinetics of salbutamol
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1401185/pdf/brjclinpharm00122-0093.pdf
http://onlinelibrary.wiley.com/doi/10.1002/cpt1972136861/full
https://link.springer.com/article/10.1007/BF02456001
Studies measuring urine levels following inhaled and/or oral doses
http://sci-hub.la/10.1249/MSS.0b013e3181b2e87d
http://sci-hub.la/10.1097/JSM.0b013e31823513e1
http://sci-hub.la/10.1055/s-2005-865627
http://sci-hub.la/10.1002/dta.1568
http://sci-hub.la/10.1002/dta.367
http://sci-hub.la/10.1097/jsm.0000000000000072
http://sci-hub.tw/10.1097/JSM.0b013e3181705c8c
http://sci-hub.la/10.1002/dta.1828
Performance enhancing effects of salbutamol
https://www.ncbi.nlm.nih.gov/pubmed/26197029
https://www.ncbi.nlm.nih.gov/pubmed/25077918
https://www.ncbi.nlm.nih.gov/pubmed/23559124
https://www.ncbi.nlm.nih.gov/pubmed/22230921
https://www.ncbi.nlm.nih.gov/pubmed/17264145
https://www.ncbi.nlm.nih.gov/pubmed/16687481
https://www.ncbi.nlm.nih.gov/pubmed/16195983
https://www.ncbi.nlm.nih.gov/pubmed/16195982
https://www.ncbi.nlm.nih.gov/pubmed/15459835
https://www.ncbi.nlm.nih.gov/pubmed/11071049
https://www.ncbi.nlm.nih.gov/pubmed/10926623
https://www.ncbi.nlm.nih.gov/pubmed/10912897
https://www.ncbi.nlm.nih.gov/pubmed/9200320
https://www.ncbi.nlm.nih.gov/pubmed/8587482
https://www.ncbi.nlm.nih.gov/pubmed/3293733
Studies of tolerance to salbutamol
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1975.tb00557.x/pdf
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1974.tb00255.x/full
http://www.atsjournals.org/doi/abs/10.1164/arrd.1980.121.6.973
http://www.sciencedirect.com/science/article/pii/S0091674999701788
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1975.tb00557.x/pdf
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1974.tb00255.x/full
http://www.atsjournals.org/doi/abs/10.1164/arrd.1980.121.6.973
http://www.sciencedirect.com/science/article/pii/S0091674999701788
http://www.sciencedirect.com/science/article/pii/014067369392695P
http://erj.ersjournals.com/content/21/5/810.long
Studies of metabolic effects of salbutamol, including weight loss and muscle growth
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2439523/#bib104
http://dmd.aspetjournals.org/content/39/5/864.long
http://dmd.aspetjournals.org/content/35/10/1797.long
https://www.ncbi.nlm.nih.gov/pubmed/26239482
https://www.ncbi.nlm.nih.gov/pubmed/7916118
Studies of amount of salbutamol inhaled under various conditions
http://sci-hub.la/10.1016/j.pupt.2017.06.004
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1806-37132011000600008&lng=en&nrm=iso&tlng=en
Urine specific gravity levels in cyclists
http://sci-hub.la/10.1123/ijsnem.2015-0188
http://sci-hub.la/10.1519/JSC.0b013e318240f677
http://sci-hub.la/10.1111/sms.12343
http://sci-hub.la/10.1097/JSM.0b013e3181b47c93
http://sci-hub.la/10.1136/bjsm.2008.049551
http://sci-hub.la/10.1186/1550-2783-11-12
http://sci-hub.la/10.1258/smj.2011.011287
http://sci-hub.la/10.1080/15438627.2011.582827
http://sci-hub.la/10.4085/1062-6050-49.3.85
http://sci-hub.la/10.1007/s00421-011-2024-y
http://sci-hub.la/http://journals.humankinetics.com/doi/abs/10.1123/ijspp.2012-0369
Legal issues, including WADA protocols and cases of other athletes
http://sci-hub.tw/10.1002/dta.2184
http://sci-hub.la/10.1385/CRIAI:31:2:259
http://www.cyclingnews.com/news/innocently-guilty-the-petacchi-case/
http://autobus.cyclingnews.com/news.php?id=news/2007/aug07/aug06news2
http://autobus.cyclingnews.com/news.php?id=news/2007/jun07/jun13news2
http://autobus.cyclingnews.com/news/?id=2003/mar03/mar24news2
https://jurisprudence.tas-cas.org/Shared%20Documents/1362,%201393.pdf
http://www.tas-cas.org/fileadmin/user_upload/Award__FINAL_.pdf
https://www.wada-ama.org/sites/default/files/resources/files/wada-td2017dl-v2-en_0.pdf