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The bile salt export pump (BSEP/Bsep/ABCB11) and multidrug resistance-associated protein 2 (MRP2/Mrp2/ABCC2) are involved in bile acid-dependent and -independent bile secretion, respectively. It has been reported that bosentan, an endothelin receptor antagonist, inhibits Bsep, which may lead to cholestatic liver injury due to the intracellular accumulation of bile salts, while increasing bile salt-independent bile flow. Thus, in this study, the effects of bosentan on BSEP/Bsep and MRP2/Mrp2 were evaluated using membrane vesicles derived from Spodoptera frugiperda (Sf) 9 cells, which express these transporters. The adenosine 5'-triphosphate (ATP)-dependent uptake of (3)H-taurocholic acid into membrane vesicles for BSEP/Bsep was inhibited by bosentan, and its IC(50) values were 76.8 and 101 microM for BSEP and Bsep, respectively. In contrast, bosentan stimulated the MRP2/Mrp2-mediated ATP-dependent vesicular transport of (3)H-estradiol 17beta-glucuronide by shifting the sigmoidal dependence of transport rate on substrate concentration to a more hyperbolic one. Collectively, these results suggest that bosentan inhibits BSEP in humans with a similar potency to rats, and that increased bile salt-independent flow in rats by bosentan is at least partly attributable to the activation of Mrp2., (Copyright 2006 John Wiley & Sons, Ltd.)

A 20-day, nonrandomized, open-label, placebo-controlled study was performed to investigate whether concomitant administration of tamsulosin (0.8 mg) affects the pharmacokinetic and safety profile of intravenous digoxin (0.5 mg) in healthy subjects. Ten healthy subjects aged 21-39 years received a single oral dose of placebo on study days 1-8 and tamsulosin on days 9-18. Tamsulosin was initiated at 0.4 mg/day and the dose was increased to 0.8 mg/day from day 11. On days 2 and 15, subjects received a single intravenous dose of digoxin (0.5 mg). Safety monitoring was carried out throughout the study. Following digoxin administration, blood was drawn and urine collected over a 96-h period for pharmacokinetic determinations. Plasma tamsulosin concentrations were measured at regular intervals after dosing on day 15. The digoxin pharmacokinetic parameters with and without concomitant tamsulosin were compared. No significant difference was observed, and no irregularity was found in the plasma tamsulosin concentration data. Six subjects experienced adverse events while receiving placebo and seven while on tamsulosin. The most frequent adverse event was mild dizziness reported by four subjects. Moderate chest pain was reported in two subjects, but this was not considered to be related to the administration of the study medications. Some significant changes in vital signs were observed; however, none was accompanied by symptoms of medical concern. These changes were not temporally related to the administration of study drugs. Thus, concurrent administration of digoxin with tamsulosin did not produce any change in the pharmacokinetics of digoxin and the safety profile was acceptable. As reflected in the prescribing information for tamsulosin, no adjustment in tamsulosin dosing is required when it is administered concomitantly with digoxin.

We performed a single-blind, sequential-design study to investigate the effects of concomitant oral tamsulosin 0.8 mg/day on the pharmacokinetics and safety of intravenous theophylline 5 mg/kg in healthy subjects. Ten healthy volunteers aged 19-39 years received placebo on study days 0, 1, 2 and 10 and tamsulosin on days 3-9. Theophylline was administered intravenously on days 1 and 9. Theophylline and tamsulosin pharmacokinetic data were determined following administration of the drugs on days 1 and 9 and day 9, respectively. No differences were observed in theophylline pharmacokinetic parameters with and without concomitant tamsulosin, and there were no abnormalities in tamsulosin pharmacokinetic data. Some significant changes in vital signs and a number of mild adverse reactions were reported, but the overall safety profile of tamsulosin and theophylline was acceptable. The results of the study suggest that no dose adjustment in tamsulosin is necessary when it is administered concomitantly with theophylline.

Objective: To investigate the factors that affect the plasma protein binding of tamsulosin in patients with lowered renal function compared with that in healthy subjects and to evaluate the possibility of binding interactions., Methods: Blood was donated from patients with renal dysfunction and from healthy subjects. The binding of 14C-tamsulosin to plasma proteins was determined by the ultrafiltration method. In addition, plasma protein binding interactions were investigated between tamsulosin and other drugs used concomitantly., Results: The mean percentage of unbound 14C-tamsulosin was 0.90% in the healthy subjects (control) and was 0.71% in the patients. The unbound fraction in the patients with alpha1-acid glycoprotein (alpha1-AGP) levels over 0.9 mg/ml was significantly lower than that in the healthy subjects. In contrast, the unbound fraction in the patients with alpha1-AGP levels less than 0.7 mg/ml, which is the mean normal level, was almost equal to the control levels. A significant correlation existed between the Cb/Cu of tamsulosin and plasma alpha1-AGP level (r2 = 0.580, P < 0.001), while no correlation existed between the Cb/Cu and plasma albumin level (r2 = 0.021, P = 0.381) in both groups. No apparent binding interactions were observed between tamsulosin and the other drugs examined., Conclusions: Tamsulosin is highly bound to alpha1-AGP. The extent of plasma protein binding of tamsulosin correlated with the alpha1-AGP level but not with the albumin level. Furthermore, there appears to be no or little possibility of binding interactions between tamsulosin and other drugs in clinically concomitant use, despite its strong binding to alpha1-AGP.

1. The in vitro human liver metabolism of the alpha1-adrenoceptor blocker tamsulosin was investigated. When 14C-tamsulosin was incubated with human liver microsomes, it was converted to five known urinary metabolites and at least three unknown metabolites. Of the former group, the predominant metabolite was the O-deethylated metabolite (M-1), followed by the o-ethoxyphenoxy acetic acid (AM-1) and the m-hydroxylated metabolite (M-3). 2. There was a good linear relationship between AM-1 formation and testosterone 6beta-hydroxylase activity in microsomes from each of 10 individual donors. The rate of M-1 formation also correlated with the same activity, albeit the correlation curve did not pass through the origin. By contrast, the rates of M-3 and the O-demethylated metabolite (M-4) formation correlated with dextromethorphan O-demethylase activity. 3. Ketoconazole strongly inhibited AM-1 formation and reduced that of M-1 by c. 60%. Immunoinhibition studies using anti-rat antibodies supported these results. The formation of M-3 and M-4 was inhibited by quinidine and sparteine. 4. It is concluded that formation of tamsulosin metabolites, AM-1 and M-1, is catalysed by CYP3A4 whereas that of M-3 and M-4 is catalysed by CYP2D6. However, minor contributions from other CYPs cannot be excluded.

The pharmacokinetics of tamsulosin hydrochloride, a selective alpha1-adrenoceptor antagonist, was investigated after single iv and oral dosing to rats and dogs, and oral dosing to healthy male volunteers. After iv dosing, plasma tamsulosin concentrations declined in an apparent biexponential manner with terminal half-lives of 0.32 hr in rats and 1.13 hr in dogs. Values for total blood clearance (CLB) were 6.57 l/hr/kg in rats and 1.61 l/hr/kg in dogs, suggesting "hepatic blood flow-limited" and "intermediate flow-dependent" clearance, respectively. After oral dosing, tamsulosin was rapidly absorbed and reached maximum levels within 1 hr in rats and dogs, and at 1.0-1.8 hr in humans. Values for oral clearance (CLoral) in rats, dogs, and humans were 34.5-113.6, 3.01-3. 99, and 0.031-0.041 l/hr/kg, respectively, showing wide variation among these species. The absolute bioavailability (F) increased with dose in rats (from 6.9% at 1 mg/kg to 22.8% at 10 mg/kg), but was almost constant in dogs (29.7-42.0% over the 0.3-3 mg/kg dose range). The plasma protein binding of 14C-tamsulosin in humans was much higher (98.9-99.1%) than that in rats and dogs (79.0-80.6% and 90. 2-90.3%, respectively). The ratio of blood to plasma concentrations (RB) value in rats, dogs, and humans decreased in this order (1.2, 0. 72, and 0.53, respectively), corresponding to the decrease in plasma unbound fraction (fu) in these species. These results imply that the large interspecies difference in CLoral is attributable to a difference not only in hepatic metabolism but also in protein binding among these species.

A highly sensitive method for the determination of tamsulosin hydrochloride, a structurally new type of sulphamoile derivative, in human plasma dialysate, plasma and urine has been developed by using liquid chromatography-electrospray tandem mass spectrometry (LC-MS-MS). Plasma dialysate, plasma and urine samples were extracted by brief liquid-phase extraction and analyzed using an HPLC system coupled to a mass spectrometer via an electrospray ionization interface. Selected reaction monitoring was used for the detection of tamsulosin and its internal standard. This method was validated in the concentration range 10-1000 pg/ml in plasma dialysate, 0.5-50 ng/ml in plasma, and 1-100 ng/ml in urine with sufficient specificity, accuracy and precision. The in vivo protein binding study demonstrated that the unbound tamsulosin in human plasma obtained by the equilibrium dialysis after 0.4-mg oral dosing was measurable. In addition, the percentage of unbound tamsulosin in an in vitro study (0.71-0.91%) obtained by using spiked 14C-labelled tamsulosin was slightly larger than that of the in vivo study (0.68-0.86%), indicating that the unbound concentration calculated by the product of the plasma concentration and the in vitro unbound fraction (fu) was unfavorably overestimated. These results suggest that the combination of LC-MS-MS and equilibrium dialysis method has enough sensitivity to determine the unbound concentration in clinical use and gives the concentration more exactly than the in vitro fu.

The pharmacokinetics of tamsulosin hydrochloride in patients with renal impairment were compared with those in healthy volunteers, and the factors that influenced plasma levels of tamsulosin were elucidated. A single oral dose of 0.2 mg of tamsulosin was given and blood and urine samples were obtained for 36 hours after administration. Unbound plasma concentration of tamsulosin was measured by a combination of equilibrium dialysis and liquid chromatography tandem mass spectrometry methods to examine the effect of protein binding on the pharmacokinetics of tamsulosin. Mean values for maximum concentration (Cmax) and area under the concentration-time curve (AUC) of total drug (Cmax,t and AUC1) in patients with renal impairment were 73% and 211% greater, respectively, than those in healthy volunteers. Mean Cmax and AUC of unbound drug (Cmax,u and AUCu), however, were almost the same in the two groups. A high correlation was found between alpha 1-acid glycoprotein (alpha 1-AGP) concentration and AUCt, but no correlation was found between alpha 1-AGP concentration and AUCu,0-36) or between creatinine clearance (ClCR) and AUCu,0-36). These results show that in patients with renal impairment, the pharmacokinetics of tamsulosin are affected by the change in protein binding that is associated with alteration of plasma alpha 1-AGP concentration, but are not largely affected by the decrease in the renal excretion. Although total tamsulosin levels increased as plasma protein binding increased, unbound tamsulosin levels (which are directly associated with the pharmacologic effects) remained unchanged in these patients.