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Analytical and Toxicological Aspects of Drug Incorporation into Human Hair
Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The overall purpose of this thesis was to develop analytical methods for the determination of drugs and melanin content of human hair for practical use in forensic and clinical toxicology. The thesis consists of five papers, two of which are controlled single dose studies where codeine or selegiline were administered to healthy volunteers. One patient study, looked at the concentrations of selegiline metabolites in both pigmented and senile white hairs as well as plasma. Another study involved forensic autopsy cases where the occurrence of drugs of abuse in post-mortem blood, urine and hair were compared. Finally, one in vitro study investigated the binding of [3H]-flunitrazepam to melanin. To our knowledge, the controlled dosage studies are the first to quantitatively determine the relationship between drug concentration in human hair and melanin content.

The results demonstrated that pigmentation was an important factor for the incorporation of codeine, methamphetamine, and amphetamine into human hair. The relationships could be described by exponential functions with correlations coefficients r2>0.8. We have shown that the pigmented portion of hair from grey-haired patients incorporated more methamphetamine and amphetamine than the non-pigmented portion. The mean pigmented/white-hair ratios were 3.7±1.9 and 3.0±1.2 for methamphetamine and amphetamine respectively. Segmental hair analysis showed decreasing drug-concentrations over three months as a sign of noncompliance or of instability of the drugs in hair owing to cosmetic treatment of hair or wear. In the controlled studies, we demonstrated that the drug concentration in hair was fairly constant up to one month. In the study on autopsy cases, we found that hair analysis revealed patterns of multi-drug use not found by analysis of a single blood sample. Also, in 6 of 19 cases of heroin overdose, no opiates could be detected in hair. This suggested "first" or only occasional use of heroin, which might have been a contributing factor to the overdose death, because of lack of tolerance. The results from the in vitro study showed that binding of flunitrazepam to eumelanin occurs by two mechanisms, a Langmuir-like binding and a diffusion limited binding. We propose that these are expressions of an initial binding to the melanin surface (surface binding) followed by the diffusion of drug molecules into the melanin granule (bulk binding).

Hair as a specimen for toxicological analysis has hitherto not been investigated in Sweden. This thesis address questions raised by international research on the incorporation of drugs into hair and its implications for clinical and forensic toxicology.

Melanin has been established as an important factor for incorporation and binding of certain drugs into human hair and methods that allow correction for this are presented. Together, the results from the various studies provide a framework for both future research and the start of drug analysis in hair for forensic and clinical applications in Sweden.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2001. , 60 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 709
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25674Local ID: 10050ISBN: 91-7373-149-8 (print)OAI: oai:DiVA.org:liu-25674DiVA: diva2:246222
Public defence
2001-12-12, Elsa Brändströms sal, Campus US, Linköpings univeristet, Linköping, 13:00 (English)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-03Bibliographically approved
List of papers
1. Incidence of opiates, amphetamines, and cocaine in hair and blood in fatal cases of heroin overdose
Open this publication in new window or tab >>Incidence of opiates, amphetamines, and cocaine in hair and blood in fatal cases of heroin overdose
1998 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 92, no 1, 29-38 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of the present study was to investigate the occurrence in hair, of some drugs of abuse in deaths caused by heroin overdose, in comparison to findings in blood. Blood, urine and hair samples were obtained during routine post mortem examinations. Samples were analysed for amphetamines, opiates, and cocaine. Immunometric drug screening was performed in urine and positive results confirmed with gas chromatography–mass spectrometry (GC–MS) of blood samples. All hair samples were analyzed with GC–MS. Hair samples were either incubated with methanol for determination of opiates and cocaine, or dissolved in sodium hydroxide for determination of amphetamines. All 19 blood samples were positive for morphine (0.04–0.4 μg g−1) and ten were also positive for 6-acetylmorphine (0.003–0.02 μg g−1). Thirteen of the hair samples were positive for 6-acetylmorphine and seven of which were positive also for morphine. Concentrations ranged from 0.3–7.4 and 0.3–1.3 (ng mg), respectively. Amphetamine was found in three blood samples (0.04–1.2 μg g−1) and in eleven hair samples (0.4–18.3 ng mg). Cocaine was determined in one blood sample (0.03 μg g−1) and two hair samples (0.7–6.5 ng mg). Out of the nineteen cases studied, eight showed chronic multi drug use on the basis of the results of hair analysis. In six subjects no opiates could be detected in hair, suggesting; “first” or occasional intake of heroin, which could be a contributing factor to the overdose death, because of lack of tolerance. We conclude that analysis of hair can be a useful complement to analysis of more conventional autopsy material, especially when investigating overdose deaths and previous histories of drug use and abuse.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80902 (URN)10.1016/S0379-0738(98)00003-6 (DOI)
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2017-12-07Bibliographically approved
2. Codeine Concentration in Hair after Oral Administration Is Dependent on Melanin Content
Open this publication in new window or tab >>Codeine Concentration in Hair after Oral Administration Is Dependent on Melanin Content
Show others...
1999 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 45, no 9, 1485-1494 p.Article in journal (Refereed) Published
Abstract [en]

Background: Analysis of drugs in hair has been used on a qualitative basis to estimate earlier exposure to drugs. Clinical applications are rare because of the lack of dose–response relationships in the studies performed to date, and questions remain regarding the mechanisms of drug incorporation into hair. Several human studies have shown differences in drug accumulation between pigmented and nonpigmented hair. However, the melanin concentration in hair was not determined and correlated to the amount of drug incorporated.

Methods: Nine human subjects were given codeine as a single oral dose, and plasma codeine concentrations were determined for 24 h, using gas chromatography–mass spectrometry. Hair samples were obtained weekly for a month. Total melanin, eumelanin, and codeine were measured quantitatively in hair samples by spectrophotometry, HPLC, and gas chromatography–mass spectrometry, respectively.

Results: There was an exponential relationship between codeine and melanin concentrations in hair, (r2 = 0.95 with total melanin and r2 = 0.83 with eumelanin). After normalizing the results by the area under the curve for codeine in plasma, we obtained r2 = 0.86 for codeine vs total melanin and r2 = 0.90 vs eumelanin.

Conclusions: Our results stress the importance of melanin determination when measuring drugs in hair. We postulate that analysis of drug concentration in hair may be worthwhile in the monitoring of drug compliance if the results are normalized for melanin content.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25184 (URN)9623 (Local ID)9623 (Archive number)9623 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. Incorporation of Selegiline Metabolites into Hair after Oral Selegiline Intake
Open this publication in new window or tab >>Incorporation of Selegiline Metabolites into Hair after Oral Selegiline Intake
2001 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 25, no 7, 594-601 p.Article in journal (Refereed) Published
Abstract [en]

We have previously shown that melanin in human hair has a great impact on the incorporation of codeine into hair. The present study on 10 subjects was performed to investigate whether or not these findings could also be extrapolated to other therapeutic drugs. We chose selegiline because it metabolizes to two commonly abused central stimulants, methamphetamine and amphetamine. The results would therefore also be of interest when studying the intake of such drugs and their incorporation into human hair. Selegiline and metabolites were determined by gas chromatography-mass spectrometry, total melanin by spectrophotometry, and pyrroletricarboxylic acid by high-performance liquid chromatography with ultraviolet detection. Our results show strong positive exponential relationships (y = ex) between melanin and the metabolites, which for methamphetamine improved by normalizing for plasma area under the curve. We conclude that the major metabolites of selegiline can be detected in hair up to four weeks after a single oral dose and that the incorporation closely relates to the melanin contents.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25186 (URN)10.1093/jat/25.7.594 (DOI)9625 (Local ID)9625 (Archive number)9625 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
4. Quantitative Analysis of Desmethylselegiline, Methamphetamine, and Amphetamine in Hair and Plasma from Parkinson Patients on Long-Term Selegiline Medicatio
Open this publication in new window or tab >>Quantitative Analysis of Desmethylselegiline, Methamphetamine, and Amphetamine in Hair and Plasma from Parkinson Patients on Long-Term Selegiline Medicatio
2003 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 27, no 3, 135-141 p.Article in journal (Refereed) Published
Abstract [en]

Hair and plasma from patients on long-term selegiline medication were analyzed to evaluate the relationships between plasma and hair melanin concentrations and the incorporation of the selegiline metabolites methamphetamine and amphetamine in hair, and to evaluate hair analyses for determining compliance in medication. Analyses were performed on both the whole hairs, as well as pigmented and non-pigmented hairs from gray-haired patients. Melanin was quantitated by spectrophotometry, and metabolites were quantitated by gas chromatography-mass spectrometry. Concentrations in pigmented and non-pigmented hairs differed significantly for both methamphetamine (p < 0.01) and amphetamine (p < 0.02), with mean concentration ratios being 3.69 ± 1.88 and 2.95 ± 1.16 for methamphetamine and amphetamine, respectively. Segmental analysis indicated that some patients had not been compliant with medication. We concluded that the incorporation of methamphetamine and amphetamine into hair of single individuals shows a preference for pigmented hairs over white hairs and that segmental analysis of hair may he useful when measuring compliance with medication.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26747 (URN)10.1093/jat/27.3.135 (DOI)11342 (Local ID)11342 (Archive number)11342 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
5. Characterization of [3H]flunitrazepam binding to melanin
Open this publication in new window or tab >>Characterization of [3H]flunitrazepam binding to melanin
Show others...
2001 (English)In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 298, no 2, 259-264 p.Article in journal (Refereed) Published
Abstract [en]

In both clinical and forensic toxicology, the analysis of hair for drugs is an important tool to determine drug use in the past or to verify abstinence from illegal drugs during extended periods. Melanin is proposed as one of the factors that influences drug incorporation to hair and we have characterized the binding of the drug flunitrazepam to melanin in vitro. The drug was 3H labeled and melanin granules from cuttlefish, Sepia officinalis, were used according to the suggested standard for melanin studies. We observed a rapid Langmuir-like binding followed by a slower diffusion-limited binding that may be interpreted as an initial surface binding followed by deeper bulk binding. From three concentrations of melanin, with a 60-min incubation time, a mean saturation value of 180 ± 20 pmol/mg was calculated. The binding of a group of benzodiazepines and tranquilizers was compared to the binding of [3H]flunitrazepam by means of displacement experiments. These drugs showed binding characteristics similar to [3H]flunitrazepam except phenobarbital, which had a lower affinity to melanin. The method presented in this study allowed measurements with low melanin and drug concentrations and it has the strength of directly measuring the amount of drug bound to melanin, in contrast to previous indirect methods.

Keyword
Affinity, Benzodiazepines, Binding, Hair, Melanin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-47156 (URN)10.1006/abio.2001.5364 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved

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