Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Tamsulosin metabolism involves both CYP2D6 and 3A4. However, data on potential drug-drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4 are limited and information on potential pharmacodynamic consequences of such pharmacokinetic interactions is missing. WHAT THIS STUDY ADDS: This study provides information on the drug-drug interactions of tamsulosin with strong CYP2D6 and strong CYP3A4 inhibitors after single dose administration in healthy subjects. AIM: To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin. METHODS: Two open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers). RESULTS: Co-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C(max) and AUC(0,∞) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2) ) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once daily with a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C(max) and AUC(0,∞) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing. CONCLUSION: The exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing.

Upregulation of phospholipase d expression and activation in ventricular pressure-overload hypertrophy.

Evidence for a role of phospholipase D (PLD) in cellular proliferation and differentiation is accumulating. We studied PLD activity and expression in normal and hypertrophic rat and human hearts. In rat heart, abdominal aortic banding (constriction to 50% of original lumen) caused hypertrophy in the left ventricle (as shown by weight index and ANP expression) by about 15% after 30 days without histological evidence of fibrosis or signs of decompensation and in the right ventricle after 100 days. The hypertrophy was accompanied by small increases of basal PLD activity and strong potentiation of stimulated PLD activity caused by 4beta-phorbol-12beta,13alpha-dibutyrate (PDB) and by phenylephrine. The mRNA expressions of both PLD1 and PLD2 determined by semiquantitative competitive RT-PCR were markedly enhanced after aortic banding. In the caveolar fraction of the rat heart, PLD2 protein determined by Western blot analysis was upregulated in parallel with the expression of caveolin-3. A similar induction of PLD mRNA and protein expression was observed in hypertrophied human hearts of individuals (39-45-year-old) who had died from non-cardiac causes. In conclusion, PLD1 and PLD2 expressions were strongly enhanced both in rat and human heart hypertrophy, which may be responsible for the coincident potentiation of the PLD activation by alpha-adrenoceptor and protein kinase C stimulation. These results are compatible with a significant role of PLD activation in cell signaling of ventricular pressure-overload hypertrophy.

Modulation of cellular cholesterol alters P-glycoprotein activity in multidrug-resistant cells.

The drug transporter P-glycoprotein (ABCB1) plays an important role in drug distribution and elimination, and when overexpressed it may confer multidrug resistance (MDR). P-glycoprotein is localized in the plasma membrane, especially within rafts and caveolae, characterized as detergent-resistant membranes (DRMs). This study investigated the effect of cholesterol depletion and repletion as well as saturation on subcellular localization and function of P-glycoprotein to determine the effect of DRM localization on P-glycoprotein-mediated drug efflux. In L-MDR1 overexpressing human P-glycoprotein, cholesterol depletion removed P-glycoprotein from the raft membranes into non-DRM fractions, whereas repletion fully reconstituted raft localization. P-glycoprotein function was assessed by realtime monitoring with confocal laser scanning microscopy using BODIPY-verapamil as substrate. Cholesterol depletion reduced P-glycoprotein function in L-MDR1 cells resulting in intracellular substrate accumulation (159% +/- 43, p < 0.001; control = 100%). Cholesterol repletion reduced intracellular substrate fluorescence (120% +/- 36, p < 0.001) and restored the transporter activity. Addition of surplus cholesterol (saturation) even enhanced drug efflux in L-MDR1 cells, leading to reduced intracellular accumulation of BODIPY-verapamil (69% +/- 10, p < 0.001). Transport of BODIPY-verapamil in cells not expressing human P-glycoprotein (LLC-PK1) was not susceptible to cholesterol alterations. These results demonstrate that cholesterol alterations influence P-glycoprotein localization and function, which might contribute to the large interindividual variability of P-glycoprotein activity known from in vivo studies.

Cholesterol modulates P-glycoprotein activity in human peripheral blood mononuclear cells.

P-glycoprotein (P-gp) is expressed in a wide range of cell types including peripheral blood mononuclear cells (PBMCs) where it may restrict intracellular accumulation of substrates like antineoplastic agents, HIV protease inhibitors, or rhodamine123. P-gp is known to be located in membrane microdomains, whose structure and function are susceptible to cholesterol alterations. This study evaluated the effect of cholesterol alteration in human PBMCs on P-gp activity. Whereas cholesterol depletion had no effect, cholesterol repletion of depleted cells significantly decreased intracellular rhodamine123 concentrations in lymphocytes to 32.2%+/-2.7 (p<0.001) and to 41.9%+/-3.5 (p<0.001) in monocytes. After cholesterol saturation of native cells intracellular rhodamine123 fluorescence decreased to 12.4%+/-1.6 (p<0.001) in lymphocytes and 12.9%+/-3.5 (p<0.001) in monocytes. These data demonstrate that elevated cellular cholesterol levels can markedly increase P-gp activity in human PBMCs.