METABOLIC AND PHARMACOKINETIC STUDIES OF BENZTROPINE AND TRIHEXYPHENIDYL
| dc.creator | He, Handan | |
| dc.date.accessioned | 2023-11-07T15:35:12Z | |
| dc.date.available | 2023-11-07T15:35:12Z | |
| dc.date.issued | 1994-10 | |
| dc.date.submitted | October 1994 | en_US |
| dc.description.abstract | Benz trop ine (3-diphenylmethoxytropine) and trihexyphenidy1(1-cyclohexyl-phenyl-3-piperidinopropan-1-ol) are synthetic anticholinergic drugs used in the treatment of Parkinson's disease and neuroleptic-induced Parkinsonism. Although the drugs have been used clinically for many years, their pharmacokinetics have not been previously determined. This seems to be due to the absence of sensitive and specific methods for assaying the drugs in biological fluids. Therefore, it was an analytical challenge to develop very sensitive and specific methods to study pharmacokinetics for benztropine and trihexyphenidyl. Radioimmunoassay (RIA) as an alternative analytical procedure to chemical analyses was thought to provide the ultrasensitivity required for trace analysis of these drugs. The assessment of specificity in RIA and development of drug specific antibodies require knowledge of the metabolic profile of the drug(s) in question. Therefore, a systematic investigation of the metabolism of each benztropine and trihexyphenidyl was undertaken. Following oral administration of benztropine, phase-I metabolites, benztropine N-oxide, N-desmethylbenztropine, tropine, 4'-hydroxybenztropine, N-desmethy1-4'- hydroxybenztropine, 4 ' -hydroxybenztropine N-oxide and methoxy- 4'-hydroxybenztropine, together with unmetabolized ivbenztropine, were isolated and identified in rat urine and bile by GC-electron impact mass spectrometry i(EI GC/MS), micro-column LC-electrospray mass spectrometry (ES LC/MS) and HPLC followed by mass analysis. In addition, four intact glucuronides corresponding to the hydroxylated metabolites of benztropine were also identified by HPLC and ES/MS analysis. The same metabolites were also identified in human plasma and urine. These results provided the first systematic report of the metabolic profile of benztropine in rats and humans. 1-Hydroxycyclohexyl-phenyl-3-piperidinopropan-l-ol (hydroxytrihexyphenidyl) and trihexyphenidyl N-oxide were detected in human plasma and rat bile after oral dosing of trihexyphenidyl by direct comparison with authentic samples. 1-Keto-cyclohexyl-phenyl-3-piperidinopropan-l-ol (keto- trihexyphenidyl), 1-keto-hydroxycyclohexyl-pheny1-3- piperidinopropan-l-ol (keto- hydroxytrihexyphenidyl), 1- dihydroxycyclohexyl-phenyl-3-piperidinopropan-l-ol (trihexyphenidyl with two hydroxyl groups), 1-cyclohexyl-l-pheny1-1-hydroxyl propanal and 1-cyclohexyl-l-pheny1-1-hydroxyl propanoic acid were also identified by using EI GC/MS, ES LC/MS and HPLC. In addition, the LC/MS with positive and negative ES ionizations combined with a HPLC system was successfully employed in the analysis of the intact glucuronides and sulfates of hydroxylated metabolites. This is the first comprehensive report on metabolism of trihexyphenidyl in rats and humans beyond previous work which identified hydroxylated trihexyphenidyl in human urine. Two haptens, benztropine hemisuccinate and trihexyphenidyl hemisuccinate, were synthesized for the development of RIA procedures for benztropine and trihexyphenidyl, respectively. The haptens were coupled to bovine serum albumin or porcine thyroglobulin to obtain the respective hapten-protein conjugates. Polyclonal antibodies to each hapten-protein conjugate were raised in New Zealand white rabbits and the titers of the developed antisera were determined by evaluating their binding to the iappropriate, tritiated analyte. The respective antiserum, which had the highest titer and minimal cross-reactivities to major metabolites and the antipsychotic drugs such as fluphenazine, flupenthixol, chlorpromazine and haloperidol, was selected for the development of RIAs. The developed RIAs for benztropine and trihexyphenidyl were sensitive enough that they can quantitate down to 31 and 7.8 pg, respectively, using a 200 gL plasma sample. Each of the developed RIA procedures was then applied to the analysis of steady state plasma samples obtained from patients undergoing treatment with benztropine or trihexyphenidyl and plasma samples obtained from healthy volunteers after administration of a single 4-mg oral dose of vibenztropine or trihexyphenidyl. The concentration vs. time curves obtained indicated that benztropine may undergo enterohepatic recycling. The pharmacokinetic parameters for each drug in human volunteers were also estimated based on either non-compartmental model or compartmental model analyses. The RIAs developed in this work are by far the most sensitive methods for the analysis of benztropine and trihexyphenidyl. They are the only methods 1 capable of investigating the pharmacokinetics of these drugs in humans after low single oral doses. | en_US |
| dc.identifier.uri | https://hdl.handle.net/10388/15225 | |
| dc.subject | BENZTROPINE | en_US |
| dc.subject | TRIHEXYPHENIDYL | en_US |
| dc.subject | METABOLIC AND PHARMACOKINETIC STUDIES | en_US |
| dc.title | METABOLIC AND PHARMACOKINETIC STUDIES OF BENZTROPINE AND TRIHEXYPHENIDYL | en_US |
| dc.type.genre | Thesis | en_US |
| thesis.degree.department | Pharmacy and Nutrition | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |