In-vitro and in-vivo metabolism of different aspirin formulations studied by a validated liquid chromatography tandem mass spectrometry method

Michele Dei; Jessica Rizzo; Mariangela Scavone; Eti Alessandra Femia; Gian Marco Podda; Elena Bossi; Sabrina Caberlon; Marco Cattaneo; Rita Paroni

doi:10.1038/s41598-021-89671-w

May 14, 2021Scientific ReportsOpen Access

In-vitro and in-vivo metabolism of different aspirin formulations studied by a validated liquid chromatography tandem mass spectrometry method

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Why the study?

Enteric-coated aspirin may be absorbed more slowly and less efficiently, requiring proper analytical methods to study pharmacokinetics, pharmacodynamics, and metabolic fate to identify non-responders.

Does enteric-coated aspirin have different pharmacokinetics compared to plain aspirin in healthy volunteers?

Structured PICO

Does enteric-coated aspirin have different pharmacokinetics compared to plain aspirin in healthy volunteers?

P

Population

6 healthy volunteers (3 men, 3 women, aged 37-63 years) and in vitro whole blood/plasma samples

I

Intervention

Enteric-coated aspirin (EC-ASA) 100 mg orally for 7 days

C

Comparator

Plain aspirin (plain-ASA) 100 mg orally for 7 days

O

Outcome

Pharmacokinetics (tmax, AUC) of aspirin and salicylic acid, and serum TxB2 levelssurrogate

A newly validated LC-MS/MS method demonstrates that while enteric-coated aspirin has delayed and more variable absorption compared to plain aspirin, both formulations effectively suppress thromboxane B2 production after 7 days of administration.

Implication

Validated LC-MS/MS method enables ASA pharmacokinetic studies; leaves open clinical utility for non-responder identification.

Abstract

Low-dose aspirin (ASA) is used to prevent cardiovascular events. The most commonly used formulation is enteric-coated ASA (EC-ASA) that may be absorbed more slowly and less efficiently in some patients. To uncover these “non-responders” patients, the availability of proper analytical methods is pivotal in order to study the pharmacodynamics, the pharmacokinetics and the metabolic fate of ASA. We validated a high-throughput, isocratic reversed-phase, negative MRM, LC–MS/MS method useful for measuring circulating ASA and salicylic acid (SA) in blood and plasma. ASA-d4 and SA-d4 were used as internal standards. The method was applied to evaluate: (a) the "in vitro" ASA degradation by esterases in whole blood and plasma, as a function of time and concentration; (b) the "in vivo" kinetics of ASA and SA after 7 days of oral administration of EC-ASA or plain-ASA (100 mg) in healthy volunteers (three men and three women, 37–63 years). Parameters of esterases activity were Vmax 6.5 ± 1.9 and Km 147.5 ± 64.4 in plasma, and Vmax 108.1 ± 20.8 and Km 803.2 ± 170.7 in whole blood. After oral administration of the two formulations, tmax varied between 3 and 6 h for EC-ASA and between 0.5 and 1.0 h for plain-ASA. Higher between-subjects variability was seen after EC-ASA, and one subject had a delayed absorption over eight hours. Plasma AUC was 725.5 (89.8–1222) for EC-ASA, and 823.1(624–1196) ng h/mL (median, 25–75% CI) for plain ASA. After the weekly treatment, serum levels of TxB2 were very low (< 10 ng/mL at 24 h from the drug intake) in all the studied subjects, regardless of the formulation or the tmax. This method proved to be suitable for studies on aspirin responsiveness.