Background: Ageing and chronic kidney disease (CKD) affect pharmacokinetic (PK) parameters. Since mechanisms are related and remain unclear, cytochrome P450 (CYP) 3A and drug transporter activities were investigated in the elderly with or without CKD and compared to healthy adults using a microdose cocktail.Methods: Healthy young participants (n = 20), healthy elderly participants (n = 16) and elderly patients with CKD (n = 17) received, in study period 1, 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 wash-out period, healthy young participants continued to study period 2 with the microdose cocktail plus rifampicin. PK parameters including area under the plasma concentration-time curve (AUC), maximum plasma drug concentration (Cmax), and half-life were estimated before making pairwise comparisons of geometric mean ratios (GMR) between groups.Results: AUC and Cmax GMR (95% confidence interval; CI) of midazolam, a CYP3A probe substrate, were increased 2.30 (1.70–3.09) and 2.90 (2.16–3.88) fold in healthy elderly and elderly patients with CKD, respectively, together with a prolonged half-life. AUC and Cmax GMR (95%CI) of atorvastatin, another CYP3A substrate, was increased 2.14 (1.52–3.02) fold in healthy elderly and 4.15 (2.98–5.79) fold in elderly patients with CKD, indicating decreased CYP3A activity related to ageing. Associated AUC changes in the probe drug whose activity could be modified by intestinal P-glycoprotein (P-gp) activity, dabigatran etexilate, were observed in patients with CKD. However, whether the activity of pitavastatin and rosuvastatin is modified by organic anion transporting polypeptide 1B (OATP1B) and of breast cancer resistance protein (BCRP), respectively, in elderly participants with or without CKD was inconclusive.Conclusions: CYP3A activity is reduced in ageing. Intestinal P-gp function might be affected by CKD, but further confirmation appears warranted.Clinical Trial Registration:http://www.thaiclinicaltrials.org/ (TCTR 20180312002 registered on March 07, 2018)

Introduction Genetic polymorphisms of drug transporters influence drug transporter activity and alter pharmacokinetic profiles of the drugs. Organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) are important transporters encoded by solute carrier organic anion transporter family member 1B1 ( SLCO1B1 ) gene and ATP-binding cassette subfamily G member 2 ( ABCG2 ) gene, respectively. Polymorphisms in these genes are associated with increased plasma statins concentrations, statin-induced myopathy and poor response to allopurinol treatment. Purpose We explored allele and genotype frequencies of S LCO1B1 and ABCG2 genes including their predicted phenotypes in 53 Thai participants. Of these, 17 had chronic kidney disease and were on statins. Materials and Methods Genotyping analysis for SLCO1B1 c.521T>C (rs4149056), c.388A>G (rs2306283), g.-11187G>A (rs4149015), and ABCG2 c.421C>A (rs2231142) was done by using TaqMan ® Real time PCR. All were tested for Hardy–Weinberg Equilibrium. Results Most of the participants (80%) had normal function haplotypes SLCO1B1 ( *1A and *1B ) while decreased ( *5, *15, and *17 ) and unknown ( *21 ) function haplotypes were less observed. Four phenotypes of SLCO1B1 were observed: 69.81% had normal function ( *1A/*1A , *1A/*1B , and *1B/*1B ), 13.21% had intermediate function ( *1A/*17 , *1B/*15 and *1B/*17 ), 9.43% had indeterminate function ( *1A/*21 and *1B/*21 ) and 7.55% had low function ( *5/*15, *15/*15, and *15/*17 ). ABCG2 c.421A allele frequency was 25%. The frequency of ABCG2 c.421CA and AA phenotypes were 37.7% and 5.7%, respectively. The allele and genotype frequencies observed are consistent with reports in Asians. However, there were differences in major allele distributions between Asians and Caucasians for SLCO1B1 c.388A>G; SLCO1B1 c.388G were highly found in Asians, but c.388A were more observed in Caucasians. Conclusion This study showed that in the Thai population, there were 4 SNPs of SLCO1B1 and ABCG2 genes. This finding may be clinically applied to minimize inter-individual variability of drugs such a...

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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.