The application of mass spectrometry in pharmacokinetics studies

Abstract

Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion (ADME) of drugs; the respective rates of which are of fundamental importance in determining their effect on the organism to which they are administered. Pharmacokinetic studies with mass spectrometry can provide quantitative information about a compound’s half-life in the body and how quickly it is metabolized or excreted. These studies are also used to determine drug distribution, partitioning within an organism, and drug dosing regime. The latter is important in determining a drug’s therapeutic range, which is a balance between the concentration required for positive therapeutic effect versus higher doses which may have toxicological effects. Finally, pharmacokinetics is used to investigate drug dosing with regards to administration factors of age, gender, ethnicity, concomitant drugs, or diseases. Pharmacokinetic analysis involves the determination of the concentration of drugs and/or their metabolites in biological fluids, which may be present at very low concentrations. Quantitative analysis is important since a major consideration in these types of studies is to determine how much drug gets into the systemic circulation. The integration of drug concentration over time (the so-called Area-Under-TheCurve or AUC) is a measure of both how well the drug is cleared by an individual and how well the analytical system is performing. Therefore, reliable, sensitive and specific methods are required for these types of analyses. With the increased pressure on researchers and pharmaceutical companies to discover and develop novel therapeutic compounds in a rapid manner, mass spectrometry now plays a central role in pharmacokinetics studies. The initial mass spectrometric technique used in pharmacokinetics, gas chromatography/mass spectrometry (GC/MS) was limited to molecules that were either volatile or could be made thermally stable by pre-column derivatization. Derivatization is often used to improve a molecule’s ability to be vaporized and ionized with a GC/MS, yet it has significant disadvantages because many molecules are still not amenable to GC/MS analysis after derivatization and the sample handling associated with derivatization results in sample loss. More recently, liquid chromatography coupled with soft ionization techniques such as electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) with triple quadrupole mass analysis (Fig. 1), have become the most common approaches in pharmacokinetic studies. This is because