Dose–hair concentration relationship and pigmentation effects in patients on low-dose clozapine

Abstract

Several hair components have been suggested as possible molecular sites for drug binding and interaction. Of these, keratin and melanin have been investigated in some detail in order to assess the mechanisms by which the binding occurs. Substances that are positively charged at physiological pH may interact by electrostatic forces between their cationic groups and the anionic carboxylic groups on the surface of the melanin polymer. Studies in human subjects with grey hair have shown that various drugs are detectable in both the coloured (melanin rich) and white (melanin free) hair shafts of these individuals. Again this supports the proposition that keratin and hair proteins play an important role in the binding of drugs in hair. However, drugs are often found in significantly higher concentrations in pigmented hair strands than in senile white hair strands. Another interesting question is if the concentration measured in hair reflects the dose taken. Previous reports have both verified and rejected this hypothesis, but most agree that many factors have impact on the incorporation rate, melanin being one. In this study we obtained blood and hair samples from 12 grey haired patients treated with low-dose clozapine as an adjunct medication in their treatment against Parkinson disease. Each patient's hair was divided into a pigmented and a non-pigmented portion and those were analyzed separately. Clozapine and desmethylclozapine were analyzed with LC-MS-MS after extraction of the analytes from hair and plasma. Paired results from the analysis of pigmented and white hair confirmed the preference for binding to pigmented hair for both clozapine and its metabolite. A majority of the incorporated clozapine was found in the pigmented hair but, as drugs could be detected in white hair, binding to hair protein or association with other hair matrix account for a significant part of drug accumulation in hair. High correlations between dose and the measured concentration of analyte were found for both clozapine (r = 0.91) and desmethylclozapine (r = 0.88).

Segmental analysis of antidepressant and antipsychotic drugs in the hair of schizophrenic patients

“…The metabolite‐to‐drug concentration ratios in all patients' hair segments are summarized in Table . The ratios of norclozapine to clozapine in this study were in the range 0.52–1.5, with a median of 1.1, values consistent with those (range 0.70–1.6, median 1.1) reported in the literature . The ratio of 9‐OH‐risperidone to risperidone in 12 patients' hair varied from 0.0045 to 0.093, which was in accordance with the published literature (from 0.012 to 1.0) .…”

“…Sato et al and Shen et al, who found that hair concentrations of chlorpromazine and administered doses were significantly correlated (r = 0.788, P < 0.001 and r = 0.8047, P < 0.001, respectively), were in agreement with our results. Significant correlations between daily doses and hair concentrations have been reported for clozapine by Cirimele et al (r = 0.542, P < 0.07, n = 23), Shen et al (r = 0.7097, P < 0.001, n = 16), and Kronstrand et al (r = 0.914, P < 0.05, n = 12) ; additionally, a significant correlation for norclozapine was reported by Kronstrand et al (r = 0.988, P < 0.05, n = 12). These results agreed with our findings regarding the correlations for clozapine and norclozapine.…”

“…Reference values for drugs in hair are beneficial for both forensic and clinical toxicology. Numerous studies on the detection of antidepressants and antipsychotics in hair and on reference values in hair have been reported . However, there is still a lack of information on reference values for some antidepressants and antipsychotics (e.g., amisulpride, aripiprazole and its metabolite dehydroaripiprazole, perphenazine, olanzapine and its metabolite norolanzapine, and sulpiride) in hair following long‐term exposure.…”

New Challenges and Perspectives in Hair Analysis

“…Highly dissimilar (1/100) hair incorporation of zolpidem, after single administration, was hypothetically attributed to ethnic differences-in terms of melanin content-between Asian and European volunteers; [42,43] indeed, largely different zolpidem concentrations were observed also between white and black hairs of a single subject [43]. The actual incorporation of all these substances in white hair, not containing melanin, even though at lower concentration, together with the incorporation of substances that do not interact with melanin, such as EtG, prove that keratin and other hair proteins play an important role in the binding of drugs in hair [39]. The actual incorporation of all these substances in white hair, not containing melanin, even though at lower concentration, together with the incorporation of substances that do not interact with melanin, such as EtG, prove that keratin and other hair proteins play an important role in the binding of drugs in hair [39].…”

“…Following this strategy, samples are collected from subjects with gray hair, then the white and pigmented hairs are separated, and processed independently [39À41] Significantly higher concentrations were observed in pigmented hair, with respect to white hair, for cocaine, amphetamines [41], and several prescription drugs with basic properties, such as amitriptyline [40], chlorpromazine, and clozapine [39]. Following this strategy, samples are collected from subjects with gray hair, then the white and pigmented hairs are separated, and processed independently [39À41] Significantly higher concentrations were observed in pigmented hair, with respect to white hair, for cocaine, amphetamines [41], and several prescription drugs with basic properties, such as amitriptyline [40], chlorpromazine, and clozapine [39].…”