Clinical pharmacokinetics of @entity1855 , @entity594 and XXXX .

@entity1 @entity8 @entity101 @entity301 @entity1855 @entity3988 @entity591 @entity6838 @entity460 @entity594 @entity1575 @entity1121
The @entity460 antagonists @entity3988 , @entity594 and @entity1855 are widely used in the treatment of @entity301 , arterial @entity101 , certain supraventricular @entity591 and obstructive @entity1121 . During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 @entity460 antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities ( @entity3988 40 to 50%; @entity594 40 to 50%; @entity1855 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In @entity1 with @entity1575 the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas @entity8 has no impact on the pharmacokinetics of @entity3988 and @entity1855 , elimination half-life of @entity594 increases in relation to the degree of @entity8 due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of @entity460 antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. @entity460 antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between @entity6838 and these drugs is of clinical importance. @entity1855 and @entity3988 cause a significant increase in plasma @entity6838 concentrations. In contrast, @entity594 does not lead to a significant increase in the plasma @entity6838 concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal @entity6838 clearance.(ABSTRACT TRUNCATED AT 400 WORDS)
