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Liquid Chromatography-Mass Spectrometric Analysis of Tropane Alkaloids in Mammalian Samples: Techniques and Applications

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LC-MS in Drug Bioanalysis

Abstract

Tropane alkaloids (TA) are bioactive small molecules containing an esterified bicyclic tropane moiety. TA represent natural plant poisons and (semi)synthetic drugs, most of them (e.g. atropine, benzatropine, N-butyl scopolamine, cimetropium, homatropine, ipratropium, N-methyl scopolamine, scopolamine, tiotropium, trospium) antagonizing acetylcholine at muscarinic receptors (MR) and some of them (e.g. bemesetron, granisetron, scopolamine, tropisetron) antagonizing serotonin at the 5-HT3 receptor (5-HT3R). Therapeutic effects on MR include mydriasis, spasmolysis of the gastrointestinal tract, overactive bladder and of the respiratory system. Due to their binding to the 5-HT3R, TA are used as antiemetic to treat vomiting and nausea. In addition, a few TA interact with α1-adrenoreceptors thus being used to improve blood flow for the treatment of septic shock (e.g. anisodamine, anisodine). Furthermore, ingestion of plants containing natural TA such as hyoscyamine and scopolamine may cause fatal intoxications.

Determination of TA is required for pharmacokinetic and distribution studies, to elucidate biotransformation in vivo and in vitro as well as to identify and quantify any poison in toxicological and forensic samples. For this purpose LC-MS-based methods are often applied. The present chapter comprehensively introduces and discusses diverse LC-MS procedures for 19 natural and synthetic TA that are of relevance as drug and poison. Individual compounds are briefly introduced providing basic pharmacological information. Their physico-chemical properties are addressed exemplifying the impact on sample preparation (e.g. precipitation, liquid–liquid extraction, solid-phase extraction) and chromatographic separation. Mass analyzers and scan modes used following electrospray and atmospheric pressure chemical ionization are commented and statistical evaluation of their frequency of use is illustrated. MS/MS-based metabolite identification strategies applied to TA analysis are pointed out. At least diverse fields of applications are categorized to review several examples of PK, distribution, and biotransformation studies as well as toxicological analysis. Concluding remarks point out potential future trends and possibilities of LC-MS in clinical pharmacology.

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Abbreviations

5-HT3R:

5-Hydroxytryptamine (serotonin) receptor

ACN:

Acetonitrile

Ada:

Anisodamine

Adi:

Anisodine

AGP:

Alpha-glycoprotein

APCI:

Atmospheric pressure chemical ionization

API:

Active pharmaceutical ingredient

Atr:

Atropine

AtrE:

Atropinesterase

BBB:

Blood–brain barrier

Becg:

Benzoylecgonine

Beme:

Bemesetron

Benz:

Benztropine

BuS:

N-butyl-scopolamine

CID:

Collision-induced dissociation

Cim:

Cimetropium

CNS:

Central nervous system

Coc:

Cocaine

COPD:

Chronic obstructive pulmonary disease

Da:

Dalton

EBQ1Q2 :

Double focusing sector field mass spectrometer

EE:

Ethylacetate

ESI:

Electrospray ionization

Et2O:

Diethylether

FA:

Formic acid

FAB:

Fast atom bombardment

GIT:

Gastrointestinal tract

glucu:

Glucuronide conjugate

Gran:

Granisetron

Hep-SA:

Heptanesulfonic acid

HPLC:

High-performance liquid chromatography

hyo:

Hyoscyamine

IBS:

Irritable bowel syndrome

Ipra:

Ipratropium

iso:

Isocratic

IT:

Ion trap

lin range:

Linear range

LLE:

Liquid–liquid extraction

log P :

Logarithm of octanol/water partition coefficient

MeOH:

Methanol

Me-O-tBu:

Methyl-tert butyl ether

MeS:

Methylscopolamine

MRM:

Multiple reaction monitoring

MS:

Full scan mass spectrometry

MS/MS:

Tandem mass spectrometry, product ion scan

MW:

Mono-isotopic molecular weight

n.s.:

Not specified

OAc:

Acetate

OP:

Organophosphorus compound

QqQ:

Triple quadrupole mass spectrometer

QTA:

Quaternary tropane alkaloid

ref:

Reference

Sat:

Satropane

Scp:

Scopolamine

SIM:

Selected ion monitoring

Solv:

HPLC solvent

SPE:

Solid-phase extraction

SQ:

Single quadrupole mass spectrometer

T:

Temperature

TA:

Tropane alkaloid

Tio:

Tiotropium

Trop:

Tropisetron

Tros:

Trospium

TSP:

Thermospray

TTA:

Tertiary tropane alkaloids

WHO:

World Health Organisation

α1-AR:

α1-Adrenoreceptor

α7-nAChR:

α7-Nicotinic receptor

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  1. Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937, Munich, Germany

    Harald John

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  1. , Department of Experimental Therapeutics, University of Texas MD Anderson Cancer C, El Rio Street 8000, Houston, 77054, USA

    Q. Alan Xu

  2. , Department of Experimental Therapeutics, University of Texas MD Anderson Cancer C, El Rio Street 8000, Houston, 77054, USA

    Timothy L. Madden

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John, H. (2012). Liquid Chromatography-Mass Spectrometric Analysis of Tropane Alkaloids in Mammalian Samples: Techniques and Applications. In: Xu, Q., Madden, T. (eds) LC-MS in Drug Bioanalysis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-3828-1_11

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