Pharmacokinetic interaction between propranolol and the HMG‐CoA reductase inhibitors pravastatin and lovastatin.

Abstract

1 Single oral 20 mg doses of the HMG-CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four-way crossover study. 2 Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3 Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration-time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4 Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5 These decreases in systemic drug concentrations may reflect enhanced drug first-pass hepatic clearance in the presence of propranolol. 6 The clinical significance of these changes is likely to be small.

Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling

“…study was reported in the literature 2. Eight single oral dose PKs with different doses were reported in the literature: 0.0372 mg,10 19.2 mg,2 20 mg,11, 12 40 mg,13, 14, 15 and 60 mg 16. Clinical studies used for the PBPK model development: i.v.…”

“…Clinical studies used for the PBPK model development: i.v. dose of 9.4 mg 2 and oral dose of 40 mg13, 14, 15; clinical studies used for the PBPK model verification: oral dose of 0.0372 mg,10 19.2 mg,2 20 mg,11, 12 and 60 mg 16…”

“…The model was further verified with additional oral PK data from doses of 0.0372 mg,10 19.2 mg,2 20 mg,11, 12 and 60 mg 16. The simulation of oral PK was conducted using virtual population of healthy subjects (10 trials of 23 individuals per trial) with body weight of 70 kg, age ranging from 18 to 25 years, with 53% women.…”

Steady state serum concentrations of pravastatin and digoxin when given in combination.

“…Although there were small (23% and 26%) increases in the mean AUC and Cmax values of pravastatin during co-administration of digoxin, the values of these parameters were within the ranges reported following single or multiple therapeutic doses of pravastatin [2][3][4]9] [10].…”

“…The pharmacokinetics of pravastatin appear linear for AUC and Cmax with respect to dose [2]. The elimination half-life of pravastatin is about 1.5 h; it is 50% to 60% bound to plasma proteins and is eliminated equally by renal and non-renal routes [3][4][5]. Pravastatin is detected in plasma as the parent compound together with two of its much less active metabolites, SQ 31,906 (the 3ot-hydroxy isomer) and SQ 31,945 (the tri-hydroxy metabolite) (Figure 1).…”