Gregory McIntire (Presenter)
Ameritox, LTD
Bio: Dr. McIntire is the Director of Research and Development at Ameritox, Ltd, a leader in Medication Monitoring. With over 30 years of experience in R&D, he oversees the management of new method development for medication testing in human urine and oral fluids from inception through validation and verification, and launch in production. Dr. McIntire earned his PhD in Chemistry (with a minor in biochemistry) from the University of Delaware. He is co-inventor on 48 patents and has published over 55 journal articles in technical areas as diverse as ophthalmology, oncology, diagnostic imaging, and particulate drug delivery (e.g., nanocrystals, liposomes, emulsions, suspensions, etc.), paclitaxel prodrugs, and fatty acid prodrugs.
Authorship: Oneka T. Cummings, Erin C. Strickland, Alexandra Clinkscales, Jeffrey Enders, and Gregory L. McIntire
Ameritox, Ltd., 486 Gallimore Dairy Road, Greensboro, NC 27409
| Short Abstract Haloperidol (Haldol®) is a typical antipsychotic prescribed for the treatment of acute symptoms of schizophrenia. adherence to haloperidol therapy is monitored by evaluating levels of haloperidol and one or more metabolites reported to be present in urine at approximately 2 and 4% of the total dose. Unchanged Haldol® has been reported to be present in urine at less than 1% of the administered dose with no evidence of glucuronidation of the parent drug (Baselt, 10th ed). This work demonstrates that the parent drug is excreted in urine as the glucuronide and that hydrolysis can yield much higher levels of parent drug upon LC/MSMS analysis than observed upon direct injection. |
Long Abstract
Introduction
Haloperidol (Haldol®) is a typical antipsychotic prescribed for the treatment of acute symptoms of schizophrenia and many other mental health symptoms including Tourette syndrome and delirium. Potential drug adherence has been shown to be low in patients with schizophrenia at 19% adherent (Millet, DeGeorge, et al.). A different report suggested that Haldol® patients are approximately 63.5% adherent overall regardless of disease as determined from patient samples with prescriptions (Millet, Ko, et al.). Typically, adherence to haloperidol therapy is monitored by evaluating levels of haloperidol and one or more metabolites reported to be present in urine at approximately 2 and 4% of the total dose. In fact, unchanged Haldol® has been reported to be present in urine at less than 1% with no evidence of glucuronidation of the parent drug (Baselt, 10th ed). These low levels of parent drug and/or metabolites after dosing increase the possibility of false negative monitoring results. Such false negative reports can improperly induce a clinician (e.g., a physician or psychiatrist) to alter a potentially compliant subject’s Haldol® therapeutic regimen when alteration is unwarranted.
Methods
Patients that were either prescribed the medication and/or were previously tested in-house as positive for haloperidol were analyzed on an Agilent LC-QTOF system (Agilent 6530 QTOF with Agilent 1290 LC stack system) using an existing screening method. Potential metabolic structures were programmed into the QTOF library for searching. Hydrolysis with β-glucuronidase obtained from IMCS was carried out at 60° C for 60 min (approx. 3,000 units) to confirm the presence of conjugated metabolites. Additional patient samples were tested hydrolysed and unhydrolysed using a Waters LC/MSMS (Acquity LC with a Xevo TQMS) system.
Results
Analysis of patient positive haloperidol samples with and without hydrolysis demonstrated the frequency of glurcuronidation as a metabolic pathway. Analysis of samples from patients who are prescribed Haldol® illustrated the rates of compliance for the various dosage forms of this drug from 100% for injectable Haldol® decanoate to less than 50% for the oral liquid formulation.
Conclusions
Enzyme hydrolysis coupled with LC/QTOF studies demonstrates the present of haloperidol glucuronide in patients positive for Haldol®. This paradigm shift can be very useful in testing patients for adherence to Haldol® therapy.
References & Acknowledgements:
Millet, DeGeorge, et al., Adherence to Treatment With Antipsychotic Medications Among Patients With Schizophrenia, Major Depressive Disorder, or Bipolar Disorder, American Society of Clinical Psychopharmacology, poster 58, June 2015.
Millet, Ko, et al, Mental Health Population Study: A Retrospective Review of the Incidence of Prescribed Antipsychotic Medications and Other Substances Detected in Urine, Internat’l. Soc. Bipolar Disorders, June, 2015.
R. C. Baselt. Disposition of toxic drugs and chemicals in man, 10th edition. Chemical Toxicology Institute, Foster City, CA, 2014, pp. 980-2, 1179, 1754-7.
| Description | Y/N | Source |
| Grants | no | |
| Salary | yes | Ameritox, Ltd. |
| Board Member | no | |
| Stock | no | |
| Expenses | no |
IP Royalty: no
| Planning to mention or discuss specific products or technology of the company(ies) listed above: | no |