Quantification of CYP3A and drug transporters activity in healthy young,
healthy elderly and chronic kidney disease elderly patients by a
microdose cocktail approach
Abstract
Aims: Ageing and chronic kidney disease (CKD) are known to affect
pharmacokinetics (PK) parameters. Since mechanisms are related and
remain unclear, cytochrome P450 (CYP)3A and drug transporter activity
were investigated in the elderly with or without CKD and compared to
healthy adults using a microdose cocktail. Methods: Healthy young
volunteers (n = 20), healthy elderly volunteers (n = 16) and elderly
with CKD (n = 17) received a single dose of microdose cocktail probe
containing 30 µg midazolam, 750 µg dabigatran etexilate, 100 µg
atorvastatin, 10 µg pitavastatin, and 50 µg rosuvastatin. After a 14-day
washout period, healthy young volunteers continued to study period 2
with the microdose cocktail plus rifampicin. PK parameters including
area under the concentration-time curve (AUC), maximum plasma drug
concentration (Cmax) and half-life were estimated before making pairwise
comparisons of geometric mean ratios between groups. Results: AUC and
Cmax of midazolam, a CYP3A probe substrate, were increased 2.30 and 2.90
fold in healthy elderly and elderly with CKD, respectively, leading to a
prolonged half-life. AUC and Cmax of atorvastatin, another CYP3A4 probe
substrate, was increased 2.14 fold in healthy elderly and 4.15 fold in
elderly with CKD, indicating decreased CYP3A4 activity related to
ageing. Association with PK changes in probe drugs representing activity
of OATP1B1, intestinal P-glycoprotein (P-gp), and breast cancer
resistance protein (BCRP) transporters was noticed, but were
inconclusive. Conclusions: CYP3A activity is reduced in ageing. There is
a trend in changes of OATP1B1, P-gp, and BCRP activity measured by
microdose cocktail probe drugs.