Simvastatin does not influence the intestinal P‐glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms

Abstract

Aims To evaluate whether simvastatin influences (i) the intestinal expression of P‐glycoprotein (P‐gp) and MRP2, and (ii) the disposition of the β1‐selective blocker talinolol, a substrate of these transporter proteins. Methods The disposition of talinolol after intravenous (30 mg) and single or repeated oral administration (100 mg daily) was monitored before and after chronic treatment with simvastatin (40 mg daily) in 18 healthy subjects (10 males, eight females, body mass index 19.0–27.0 kg m−2) genotyped for ABCB1, ABCC2 and SLCO1B1 polymorphisms. The steady‐state pharmacokinetics of simvastatin was evaluated before and after repeated oral talinolol administration. The duodenal expression of ABCB1 and ABCC2 mRNA before and after simvastatin treatment was quantified using real‐time reverse transcriptase‐polymerase chain reaction (TaqMan®). Results Simvastatin did not influence the expression of duodenal ABCB1 and ABCC2. There was no significant pharmacokinetic interaction between simvastatin and talinolol. Duodenal ABCB1 mRNA content was significantly correlated with the AUC0–∞ (r = 0.627, P = 0.039) and Cmax (r = 0.718, P = 0.013) of oral talinolol. The ABCB1 and ABCC2 gene polymorphisms did not influence simvastatin and talinolol disposition. The half‐life of the latter was significantly shorter in the nine carriers with a SLCO1B1*1b allele compared with the seven subjects with the wild‐type SLCO1B1*1a/*1a genotype (12.2 ± 1.6 h vs. 14.5 ± 1.4 h, P = 0.01). Conclusions Simvastatin does not influence the intestinal expression of P‐gp and MRP2 in man. There was no pharmacokinetic interaction between talinolol and simvastatin during their chronic co‐administration to healthy subjects.

The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells

“…Actually, in a multicenter study performed by Pearson et al (2005) [35] which determined the extend of reduction in LDL-C after addition of ezetimibe to ongoing statin therapy of hypercholesterolemic subjects, they could observe that simvastatin was the only drug that had a dose dependent effect when combined with ezetimibe, and a dose of 80 mg/day was more effective than the maximum dose for other statins. Disagreeing with our data, simvastatin treatment did not influence the expression of duodenal ABCC2 expression in healthy individuals [36] . However, the discrepancy between our results and the above is that the expression of ABC transporters in Caco-2 cells, as previously discussed, is more similar to the colon than to the small intestine.…”

Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice

“…Increased intestinal P-gp function or expression can markedly affect drug pharmacokinetics, leading to decreased therapeutic effect. In humans, intestinal MDR1 mRNA is inversely correlated with oral tacrolimus concentrations (Masuda et al, 2004), cyclosporine pharmacokinetics (Masuda and Inui, 2006), and talinolol pharmacokinetics (Bernsdorf et al, 2006). Additionally, xenobiotics that alter the function of P-gp can cause drug-drug interactions; for example, St. John's Wort induces intestinal P-gp, leading to decreased talinolol area under the curve in human subjects (Schwarz et al, 2007).…”

In Vivo Probes of Drug Transport: Commonly Used Probe Drugs to Assess Function of Intestinal P-glycoprotein (ABCB1) in Humans

“…Intestinal expression of P-glycoprotein in humans is highly variable and regioselective. ABCB1mRNA and P-glycoprotein content in the duodenum vary in healthy white subjects by a factor of three to ten (Bernsdorf et al 2006;Greiner et al 1999;Lown et al 1997;Oswald et al 2006;Schwarz et al 2007;Siegmund et al 2002b). However, the expression level is low in the duodenum and proximal jejunum and in the ascending colon.…”

“…After intravenous administration (30 mg, 18 healthy subjects), about 43% of the dose are excreted with the urine, and about 22% is recovered in the feces. After oral administration (100 mg), about 30% are excreted with the urine and another 30% appear in the feces (Bernsdorf et al 2006). Renal clearance is about 150-190 ml/min which is higher than the product of nonprotein bound talinolol (f u~0 .4) and filtration rate in healthy subjects (~120 ml/min) (Bernsdorf et al 2006;Giessmann et al 2004a;Siegmund et al 2002a;Westphal et al 1996Westphal et al , 2000b.…”