Guidelines for Testing Drugs from the UN Office of Drugs and Crime
Manual for Use By National Drug Analysis Labs
United Nations 2014
https://www.unodc.org/documents/scientific/ST_NAR_30_Rev.3_Hair_Sweat_and_Oral_Fluid.pdf 67 4. General considerations in the analysis of drugs in hair, sweat and oral fluid This Manual is focused on the application of up-to-date techniques of analytical toxicology to “alternative” biological specimens such as hair, sweat and oral fluid. These biological matrices, evidently different in composition from the more tradi- tional biofluids, i.e. urine and blood, require a robust analytical methodology based on unequivocal determination of the analytes of interest obtained by accurate quali- tative and quantitative techniques, including mass spectrometric identification (e.g. GC-MS or LC-MS). • Only by adopting the accepted strategy in forensic toxicology, based on screening and confirmation on two different aliquots of the same sample, can analytical results obtained in alternative matrices achieve a high degree of reliability which is required in a forensic context. • In order to manage high routine workloads, a rapid, high throughput screen- ing w ould be ideal, whereas a confirmation of the results by chromatogra- phy coupled to mass spectrometry is always mandatory. • In addition, it is important to stress that sound analytical data do not always pro vide for a sound interpretation. In fact, because of current limited knowl- edge of the modalities/kinetics of incorporation and elimination of xenobiot- ics, the interpretation of analytical results may still be difficult. • A few considerations may be helpful for the correct use/interpretation of analytical data. The sequence of the presence of xenobiotics and their metabolites in both alternate and con ventional biological specimens tends to follow this time scheme (increasing time window of detectability): blood à oral fluid à urine à sweat (with patch sampling) à hair. This phenomenon is mostly related to pharmacokinetic properties of active principles, i.e. the mechanisms of adsorption, distribution/incorporation, metabolism and disposal of drugs and metabolites, in which the chemical-physical properties of drugs and their metabolites are crucial. A direct consequence of the diverse time course of xenobiotics in the different biological samples is that the opportunity to detect a drug consumed by a subject is related to the choice of the 68 Guidelines for testing drugs under international control in hair, sweat and or al fluid most suitable specimen. If analyses are performed in different specimens from the same subject, providing apparently contrasting results (e.g. “positive” urine result vs. “negative” blood result). This can be useful for a more detailed hypothesis on the time and manner of a drug intake. A standard interpretation is not possible and may be misleading. However, some elementary examples of interpretation of results obtained from multiple specimens are presented in table 14 [83]. In summary: • Each specimen is suitable for particular applications in relation to its specific characteristics. • Hair can be employed in workplace drug testing, dri ving licence re-granting, investigation of drug-use history, divorce litigations, child custody hearings, testing for previous intentional/unintentional drug use around a certain date, determination of gestational drug exposure, investigation of doping prac- tices, drug-facilitated crimes and post-mortem toxicology (drug-related deaths, health impairments caused by chronic drug abuse, tolerance in opi- oid death cases, chronic drug use and fatal accidents, repeated criminal poisoning, contribution to identification of a corpse, demonstration/exclu- sion of external contamination). • Oral fluid testing is mostly employed for roadside drug testing and, potentially, can be used to gather information on acute intoxication if blood cannot be collected (such as in w orkplace drug testing). • Sweat is still rarely used, mostly for monitoring drug abstinence in “on parole” control programmes and, in limited cases, in workplace drug testing. • The analysis of multiple specimens can be useful: – To better define the time and manner of exposure to one or more x enobiotics; – To confirm laboratory results in cases of doubtful clinical and anam- nestic histories. • Qualitative results (i.e. presence or absence of drugs or metabolites) in alternate matrices such as hair , sweat or oral fluid are generally well understood. • The interpretation of quantitative data, i.e. concentrations of drugs in alter - nate specimens, is still under debate, especially with regard to the dose- concentration relationship. Note Hair, because of the substantial lack of metabolism following incorporation of a drug and the extended “time window” of detectability of drugs, has the potential to Chapter 4. General considerations in the analysis of drugs in hair , sweat and oral fluid 69 be a useful tool to study the epidemiology of the prevalence of abuse of new psychoactive substances (NPS) (e.g. synthetic cannabinoids, cathinones) in popula - tions. In fact, because of their extensive metabolism, rapid kinetics, excretion and irregular mode of use, their detection in conventional biofluids is extremely ineffi- cient. In this context, the stability of the analytes when incorporated in hair and the negligible biological hazard of hair samples make them suitable for long-term stor - age and dispatch to reference laboratories hosting the required, highly sophisticated instrumentation. As already mentioned, however, contamination can rarely be ruled out completely, neither can “on-purpose” hair “cleaning” from drug residues. A recent review of the forensic toxicological strategies adopted to face the problems of detection and measurement of new psychoactive substances in biological samples has been published by Favretto et al. [160]. Table 14. Multiple specimen testing: interpretation of apparently discordant results [83] Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Time of urine collection too close to time of drug use + – Highly protein-bound drugs may be poorly distributed to oral fluid, e.g. benzodiazepines + – Low drug dose; Sampling time outside detection “window” + – Low drug dose; Low binding affinity to hair matrix (e.g. cannabinoids); Hair treatments (e.g. bleaching, straighteners); Sampling time outside detection “window” – + Long interval after dosing; Concentration affects of kidney function + – Long interval after dosing; Concentration affects of kidney function; Highly protein-bound drug; Sampling time outside detection “window” 70 Guidelines for testing drugs under international control in hair, sweat and or al fluid Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair
PATCH
PCHM
Listening pleasure
67 4. General considerations in the analysis of drugs in hair, sweat and oral fluid This Manual is focused on the application of up-to-date techniques of analytical toxicology to “alternative” biological specimens such as hair, sweat and oral fluid. These biological matrices, evidently different in composition from the more tradi- tional biofluids, i.e. urine and blood, require a robust analytical methodology based on unequivocal determination of the analytes of interest obtained by accurate quali- tative and quantitative techniques, including mass spectrometric identification (e.g. GC-MS or LC-MS). • Only by adopting the accepted strategy in forensic toxicology, based on screening and confirmation on two different aliquots of the same sample, can analytical results obtained in alternative matrices achieve a high degree of reliability which is required in a forensic context. • In order to manage high routine workloads, a rapid, high throughput screen- ing w ould be ideal, whereas a confirmation of the results by chromatogra- phy coupled to mass spectrometry is always mandatory. • In addition, it is important to stress that sound analytical data do not always pro vide for a sound interpretation. In fact, because of current limited knowl- edge of the modalities/kinetics of incorporation and elimination of xenobiot- ics, the interpretation of analytical results may still be difficult. • A few considerations may be helpful for the correct use/interpretation of analytical data. The sequence of the presence of xenobiotics and their metabolites in both alternate and con ventional biological specimens tends to follow this time scheme (increasing time window of detectability): blood à oral fluid à urine à sweat (with patch sampling) à hair. This phenomenon is mostly related to pharmacokinetic properties of active principles, i.e. the mechanisms of adsorption, distribution/incorporation, metabolism and disposal of drugs and metabolites, in which the chemical-physical properties of drugs and their metabolites are crucial. A direct consequence of the diverse time course of xenobiotics in the different biological samples is that the opportunity to detect a drug consumed by a subject is related to the choice of the 68 Guidelines for testing drugs under international control in hair, sweat and or al fluid most suitable specimen. If analyses are performed in different specimens from the same subject, providing apparently contrasting results (e.g. “positive” urine result vs. “negative” blood result). This can be useful for a more detailed hypothesis on the time and manner of a drug intake. A standard interpretation is not possible and may be misleading. However, some elementary examples of interpretation of results obtained from multiple specimens are presented in table 14 [83]. In summary: • Each specimen is suitable for particular applications in relation to its specific characteristics. • Hair can be employed in workplace drug testing, dri ving licence re-granting, investigation of drug-use history, divorce litigations, child custody hearings, testing for previous intentional/unintentional drug use around a certain date, determination of gestational drug exposure, investigation of doping prac- tices, drug-facilitated crimes and post-mortem toxicology (drug-related deaths, health impairments caused by chronic drug abuse, tolerance in opi- oid death cases, chronic drug use and fatal accidents, repeated criminal poisoning, contribution to identification of a corpse, demonstration/exclu- sion of external contamination). • Oral fluid testing is mostly employed for roadside drug testing and, potentially, can be used to gather information on acute intoxication if blood cannot be collected (such as in w orkplace drug testing). • Sweat is still rarely used, mostly for monitoring drug abstinence in “on parole” control programmes and, in limited cases, in workplace drug testing. • The analysis of multiple specimens can be useful: – To better define the time and manner of exposure to one or more x enobiotics; – To confirm laboratory results in cases of doubtful clinical and anam- nestic histories. • Qualitative results (i.e. presence or absence of drugs or metabolites) in alternate matrices such as hair , sweat or oral fluid are generally well understood. • The interpretation of quantitative data, i.e. concentrations of drugs in alter - nate specimens, is still under debate, especially with regard to the dose- concentration relationship. Note Hair, because of the substantial lack of metabolism following incorporation of a drug and the extended “time window” of detectability of drugs, has the potential to Chapter 4. General considerations in the analysis of drugs in hair , sweat and oral fluid 69 be a useful tool to study the epidemiology of the prevalence of abuse of new psychoactive substances (NPS) (e.g. synthetic cannabinoids, cathinones) in popula - tions. In fact, because of their extensive metabolism, rapid kinetics, excretion and irregular mode of use, their detection in conventional biofluids is extremely ineffi- cient. In this context, the stability of the analytes when incorporated in hair and the negligible biological hazard of hair samples make them suitable for long-term stor - age and dispatch to reference laboratories hosting the required, highly sophisticated instrumentation. As already mentioned, however, contamination can rarely be ruled out completely, neither can “on-purpose” hair “cleaning” from drug residues. A recent review of the forensic toxicological strategies adopted to face the problems of detection and measurement of new psychoactive substances in biological samples has been published by Favretto et al. [160]. Table 14. Multiple specimen testing: interpretation of apparently discordant results [83] Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Time of urine collection too close to time of drug use + – Highly protein-bound drugs may be poorly distributed to oral fluid, e.g. benzodiazepines + – Low drug dose; Sampling time outside detection “window” + – Low drug dose; Low binding affinity to hair matrix (e.g. cannabinoids); Hair treatments (e.g. bleaching, straighteners); Sampling time outside detection “window” – + Long interval after dosing; Concentration affects of kidney function + – Long interval after dosing; Concentration affects of kidney function; Highly protein-bound drug; Sampling time outside detection “window” 70 Guidelines for testing drugs under international control in hair, sweat and or al fluid Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Concentration affects of kidney function; Sampling time outside detection “window” + – Concentration affects of kidney function; Low doses or single dose; Low binding affinity to hair matrix; Sampling time outside detection “window” – + Insufficient time for drug absorption; Residues in oral cavity from the latest drug intake; Sampling time outside detection “window” due to longer detection time in oral fluid – + Insufficient time for drug absorption, metabolism and excretion; Residues in oral cavity from the latest drug intake + – Insufficient time for drug absorption, metabolism and excretion; Residues in oral cavity from the latest drug intake + – Low drug dose; Low binding affinity to hair matrix; Insufficient time for drug absorption, metabolism and excretion; Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” Table 14. (continued) Chapter 4. General considerations in the analysis of drugs in hair , sweat and oral fluid 71 Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Low drug dose; Low binding affinity to hair matrix; Insufficient time for drug absorption, metabolism and excretion; Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” Table 14. (continued)
67 4. General considerations in the analysis of drugs in hair, sweat and oral fluid This Manual is focused on the application of up-to-date techniques of analytical toxicology to “alternative” biological specimens such as hair, sweat and oral fluid. These biological matrices, evidently different in composition from the more tradi- tional biofluids, i.e. urine and blood, require a robust analytical methodology based on unequivocal determination of the analytes of interest obtained by accurate quali- tative and quantitative techniques, including mass spectrometric identification (e.g. GC-MS or LC-MS). • Only by adopting the accepted strategy in forensic toxicology, based on screening and confirmation on two different aliquots of the same sample, can analytical results obtained in alternative matrices achieve a high degree of reliability which is required in a forensic context. • In order to manage high routine workloads, a rapid, high throughput screen- ing w ould be ideal, whereas a confirmation of the results by chromatogra- phy coupled to mass spectrometry is always mandatory. • In addition, it is important to stress that sound analytical data do not always pro vide for a sound interpretation. In fact, because of current limited knowl- edge of the modalities/kinetics of incorporation and elimination of xenobiot- ics, the interpretation of analytical results may still be difficult. • A few considerations may be helpful for the correct use/interpretation of analytical data. The sequence of the presence of xenobiotics and their metabolites in both alternate and con ventional biological specimens tends to follow this time scheme (increasing time window of detectability): blood à oral fluid à urine à sweat (with patch sampling) à hair. This phenomenon is mostly related to pharmacokinetic properties of active principles, i.e. the mechanisms of adsorption, distribution/incorporation, metabolism and disposal of drugs and metabolites, in which the chemical-physical properties of drugs and their metabolites are crucial. A direct consequence of the diverse time course of xenobiotics in the different biological samples is that the opportunity to detect a drug consumed by a subject is related to the choice of the 68 Guidelines for testing drugs under international control in hair, sweat and or al fluid most suitable specimen. If analyses are performed in different specimens from the same subject, providing apparently contrasting results (e.g. “positive” urine result vs. “negative” blood result). This can be useful for a more detailed hypothesis on the time and manner of a drug intake. A standard interpretation is not possible and may be misleading. However, some elementary examples of interpretation of results obtained from multiple specimens are presented in table 14 [83]. In summary: • Each specimen is suitable for particular applications in relation to its specific characteristics. • Hair can be employed in workplace drug testing, dri ving licence re-granting, investigation of drug-use history, divorce litigations, child custody hearings, testing for previous intentional/unintentional drug use around a certain date, determination of gestational drug exposure, investigation of doping prac- tices, drug-facilitated crimes and post-mortem toxicology (drug-related deaths, health impairments caused by chronic drug abuse, tolerance in opi- oid death cases, chronic drug use and fatal accidents, repeated criminal poisoning, contribution to identification of a corpse, demonstration/exclu- sion of external contamination). • Oral fluid testing is mostly employed for roadside drug testing and, potentially, can be used to gather information on acute intoxication if blood cannot be collected (such as in w orkplace drug testing). • Sweat is still rarely used, mostly for monitoring drug abstinence in “on parole” control programmes and, in limited cases, in workplace drug testing. • The analysis of multiple specimens can be useful: – To better define the time and manner of exposure to one or more x enobiotics; – To confirm laboratory results in cases of doubtful clinical and anam- nestic histories. • Qualitative results (i.e. presence or absence of drugs or metabolites) in alternate matrices such as hair , sweat or oral fluid are generally well understood. • The interpretation of quantitative data, i.e. concentrations of drugs in alter - nate specimens, is still under debate, especially with regard to the dose- concentration relationship. Note Hair, because of the substantial lack of metabolism following incorporation of a drug and the extended “time window” of detectability of drugs, has the potential to Chapter 4. General considerations in the analysis of drugs in hair , sweat and oral fluid 69 be a useful tool to study the epidemiology of the prevalence of abuse of new psychoactive substances (NPS) (e.g. synthetic cannabinoids, cathinones) in popula - tions. In fact, because of their extensive metabolism, rapid kinetics, excretion and irregular mode of use, their detection in conventional biofluids is extremely ineffi- cient. In this context, the stability of the analytes when incorporated in hair and the negligible biological hazard of hair samples make them suitable for long-term stor - age and dispatch to reference laboratories hosting the required, highly sophisticated instrumentation. As already mentioned, however, contamination can rarely be ruled out completely, neither can “on-purpose” hair “cleaning” from drug residues. A recent review of the forensic toxicological strategies adopted to face the problems of detection and measurement of new psychoactive substances in biological samples has been published by Favretto et al. [160]. Table 14. Multiple specimen testing: interpretation of apparently discordant results [83] Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Time of urine collection too close to time of drug use + – Highly protein-bound drugs may be poorly distributed to oral fluid, e.g. benzodiazepines + – Low drug dose; Sampling time outside detection “window” + – Low drug dose; Low binding affinity to hair matrix (e.g. cannabinoids); Hair treatments (e.g. bleaching, straighteners); Sampling time outside detection “window” – + Long interval after dosing; Concentration affects of kidney function + – Long interval after dosing; Concentration affects of kidney function; Highly protein-bound drug; Sampling time outside detection “window” 70 Guidelines for testing drugs under international control in hair, sweat and or al fluid Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Concentration affects of kidney function; Sampling time outside detection “window” + – Concentration affects of kidney function; Low doses or single dose; Low binding affinity to hair matrix; Sampling time outside detection “window” – + Insufficient time for drug absorption; Residues in oral cavity from the latest drug intake; Sampling time outside detection “window” due to longer detection time in oral fluid – + Insufficient time for drug absorption, metabolism and excretion; Residues in oral cavity from the latest drug intake + – Insufficient time for drug absorption, metabolism and excretion; Residues in oral cavity from the latest drug intake + – Low drug dose; Low binding affinity to hair matrix; Insufficient time for drug absorption, metabolism and excretion; Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” Table 14. (continued) Chapter 4. General considerations in the analysis of drugs in hair , sweat and oral fluid 71 Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Low drug dose; Low binding affinity to hair matrix; Insufficient time for drug absorption, metabolism and excretion; Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” Table 14. (continued)
67 4. General considerations in the analysis of drugs in hair, sweat and oral fluid This Manual is focused on the application of up-to-date techniques of analytical toxicology to “alternative” biological specimens such as hair, sweat and oral fluid. These biological matrices, evidently different in composition from the more tradi- tional biofluids, i.e. urine and blood, require a robust analytical methodology based on unequivocal determination of the analytes of interest obtained by accurate quali- tative and quantitative techniques, including mass spectrometric identification (e.g. GC-MS or LC-MS). • Only by adopting the accepted strategy in forensic toxicology, based on screening and confirmation on two different aliquots of the same sample, can analytical results obtained in alternative matrices achieve a high degree of reliability which is required in a forensic context. • In order to manage high routine workloads, a rapid, high throughput screen- ing w ould be ideal, whereas a confirmation of the results by chromatogra- phy coupled to mass spectrometry is always mandatory. • In addition, it is important to stress that sound analytical data do not always pro vide for a sound interpretation. In fact, because of current limited knowl- edge of the modalities/kinetics of incorporation and elimination of xenobiot- ics, the interpretation of analytical results may still be difficult. • A few considerations may be helpful for the correct use/interpretation of analytical data. The sequence of the presence of xenobiotics and their metabolites in both alternate and con ventional biological specimens tends to follow this time scheme (increasing time window of detectability): blood à oral fluid à urine à sweat (with patch sampling) à hair. This phenomenon is mostly related to pharmacokinetic properties of active principles, i.e. the mechanisms of adsorption, distribution/incorporation, metabolism and disposal of drugs and metabolites, in which the chemical-physical properties of drugs and their metabolites are crucial. A direct consequence of the diverse time course of xenobiotics in the different biological samples is that the opportunity to detect a drug consumed by a subject is related to the choice of the 68 Guidelines for testing drugs under international control in hair, sweat and or al fluid most suitable specimen. If analyses are performed in different specimens from the same subject, providing apparently contrasting results (e.g. “positive” urine result vs. “negative” blood result). This can be useful for a more detailed hypothesis on the time and manner of a drug intake. A standard interpretation is not possible and may be misleading. However, some elementary examples of interpretation of results obtained from multiple specimens are presented in table 14 [83]. In summary: • Each specimen is suitable for particular applications in relation to its specific characteristics. • Hair can be employed in workplace drug testing, dri ving licence re-granting, investigation of drug-use history, divorce litigations, child custody hearings, testing for previous intentional/unintentional drug use around a certain date, determination of gestational drug exposure, investigation of doping prac- tices, drug-facilitated crimes and post-mortem toxicology (drug-related deaths, health impairments caused by chronic drug abuse, tolerance in opi- oid death cases, chronic drug use and fatal accidents, repeated criminal poisoning, contribution to identification of a corpse, demonstration/exclu- sion of external contamination). • Oral fluid testing is mostly employed for roadside drug testing and, potentially, can be used to gather information on acute intoxication if blood cannot be collected (such as in w orkplace drug testing). • Sweat is still rarely used, mostly for monitoring drug abstinence in “on parole” control programmes and, in limited cases, in workplace drug testing. • The analysis of multiple specimens can be useful: – To better define the time and manner of exposure to one or more x enobiotics; – To confirm laboratory results in cases of doubtful clinical and anam- nestic histories. • Qualitative results (i.e. presence or absence of drugs or metabolites) in alternate matrices such as hair , sweat or oral fluid are generally well understood. • The interpretation of quantitative data, i.e. concentrations of drugs in alter - nate specimens, is still under debate, especially with regard to the dose- concentration relationship. Note Hair, because of the substantial lack of metabolism following incorporation of a drug and the extended “time window” of detectability of drugs, has the potential to Chapter 4. General considerations in the analysis of drugs in hair , sweat and oral fluid 69 be a useful tool to study the epidemiology of the prevalence of abuse of new psychoactive substances (NPS) (e.g. synthetic cannabinoids, cathinones) in popula - tions. In fact, because of their extensive metabolism, rapid kinetics, excretion and irregular mode of use, their detection in conventional biofluids is extremely ineffi- cient. In this context, the stability of the analytes when incorporated in hair and the negligible biological hazard of hair samples make them suitable for long-term stor - age and dispatch to reference laboratories hosting the required, highly sophisticated instrumentation. As already mentioned, however, contamination can rarely be ruled out completely, neither can “on-purpose” hair “cleaning” from drug residues. A recent review of the forensic toxicological strategies adopted to face the problems of detection and measurement of new psychoactive substances in biological samples has been published by Favretto et al. [160]. Table 14. Multiple specimen testing: interpretation of apparently discordant results [83] Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Time of urine collection too close to time of drug use + – Highly protein-bound drugs may be poorly distributed to oral fluid, e.g. benzodiazepines + – Low drug dose; Sampling time outside detection “window” + – Low drug dose; Low binding affinity to hair matrix (e.g. cannabinoids); Hair treatments (e.g. bleaching, straighteners); Sampling time outside detection “window” – + Long interval after dosing; Concentration affects of kidney function + – Long interval after dosing; Concentration affects of kidney function; Highly protein-bound drug; Sampling time outside detection “window” 70 Guidelines for testing drugs under international control in hair, sweat and or al fluid Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Concentration affects of kidney function; Sampling time outside detection “window” + – Concentration affects of kidney function; Low doses or single dose; Low binding affinity to hair matrix; Sampling time outside detection “window” – + Insufficient time for drug absorption; Residues in oral cavity from the latest drug intake; Sampling time outside detection “window” due to longer detection time in oral fluid – + Insufficient time for drug absorption, metabolism and excretion; Residues in oral cavity from the latest drug intake + – Insufficient time for drug absorption, metabolism and excretion; Residues in oral cavity from the latest drug intake + – Low drug dose; Low binding affinity to hair matrix; Insufficient time for drug absorption, metabolism and excretion; Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” Table 14. (continued) Chapter 4. General considerations in the analysis of drugs in hair , sweat and oral fluid 71 Matrix Possible explanations for disparate results Blood Urine Oral fluid Sweat Hair + – Low drug dose; Low binding affinity to hair matrix; Insufficient time for drug absorption, metabolism and excretion; Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” – + Sampling time outside detection “window” Table 14. (continued)