Quantification of serum levels in mice of seven drugs (and six metabolites) commonly taken by older people with polypharmacy.

Polypharmacy (use of ≥ 5 drugs) is common in older people but has minimal pre-clinical or clinical evidence of safety or efficacy and is associated with adverse outcomes in older people. Drug-drug interactions are poorly understood beyond drug pairs. An efficient and sensitive method to measure multiple serum drugs and metabolites could inform drug dosing in polypharmacy. Development of a liquid chromatography tandem mass spectrometry method to simultaneously measure 7 drugs and 6 metabolites, and screen levels in a polypharmacy preclinical model. This method was validated for optimal recovery, matrix effect, limit of quantification (LOQ), inter and intra-day variability, and carry over. Serum samples from mice (n=5-6/group) treated with chronic oral doses of 3 polypharmacy regimens and 5 monotherapies were screened for drug and metabolite levels (metoprolol, α-hydroxymetoprolol, O-desmethylmetoprolol, omeprazole, 5-hydroxyomeprazole, omeprazole sulfone, acetaminophen, irbesartan, citalopram, oxybutynin, oxycodone, noroxycodone, oxymorphone and tenivastatin). The LOQ for the compounds ranged from 0.05-0.1ng/mL in serum. Recovery, matrix effect and inter, intra-day variability peak response were acceptable. No carry over was observed at the concentrations tested. Analytes were detectable in mice treated with these drugs and differences in drug levels were observed with different polypharmacy and monotherapy regimens. The method is sensitive and robust to measure parent drugs and metabolites simultaneously in the context of polypharmacy. Polypharmacy appeared to affect drug levels in a preclinical model. This model can be used to understand pharmacokinetics of chronic polypharmacy, which could inform prescribing and improve outcomes for older people.