Metoprolol drug elimination

In the case of metoprolol succinate and metoprolol fumarate, the maximum drug concentration in the plasma( max) and the area under the plasma drug concentration-time curve were statistically equivalent, based on a 90% conLdence interval (Sandberg et al., 1993). With fenoprdffcQmthe following administration of its calcium salt was reached somewhat later thaCmjpassociated with the sodium form (Rubin et al., 1971). This was attributed to the slower dissolution rate for the calcium salt in acidic pH. Bioavailability and the measured distribution and elimination parameters, however, were reported to be similar. 

Drugs that preferentially block the [ receptors have been developed to eliminate the unwanted bronchoconstrictor effect (p2) of propranolol seen among asthmatic patients. Cardioselective p-blockers, such as acebutolol [a se BYOO toe lole], atenolol [a TEN oh lole], and metoprolol [me TOE proe lole], antagonize receptors at closes 50 to 100 times less than those required to block p2 receptors. This cardioselectivity is thus most pronounced at low doses and is lost at high drug doses. [Note Acebutolol has some intrinsic agonist activity.]... 

The liver is the most important site of presystemic elimination because of high levels of drug-metabolizing enzymes, its ability to rapidly metabolize different types of drugs, and its unique anatomical location. The following are selected examples of drugs that are subject to considerable hepatic first-pass metabolism the 3-blockers propranolol and metoprolol the analgesics propoxyphene, meperidine, and pentazocine the antidepressants imipramine and nortriptyline and the antiarrhythmic lidocaine. 

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-11 receptor blockers (ARBs), P-blockers, and calcium channel blockers are not dosed in the clinical setting using pharmacokinetic equations. The clinical use and selection of a drug within a class of medications is determined, in part, on differences in pharmacokinetic parameters. Eor example, metoprolol is commonly used in patients with renal disease because it is metabolized in the liver. Atenolol is avoided because it is renally eliminated. Select pharmacokinetic parameters for ACE inhibitors, ARBs, P-blockers, and calcium channel blockers are listed in Tables 8.11 through 8.13. 

The elimination of most beta-blockers occurs via hepatic metabolism and/or renal excretion of the unchanged drug. While the lipophilic beta blockers, such as propranolol, are eliminated mostly by metabolism, the more hydrophilic beta blockers, such as atenolol and nadolol, are almost exclusively excreted unchanged in urine. Some aspects of the stereoselective human metabolism of propranolol and metoprolol, two widely studied beta-blockers, will be discussed here. 

The stereoselectivity in the plasma concentrations of metoprolol is mostly related to the stereoselective metabolism and first-pass effect of the drug. A slight stereoselectivity in the renal clearance of the drug in favor of R( )-metoprolol (Table 3) virtually has no effect on the plasma stereoselectivity because of the negligible contribution of this pathway to the overall elimination of the drug. Whereas a preferential metabolism of ( )-metoprolol in extensive metabolizers of debrisoquine results in a (—) ( ) AUC ratio of 1.37 0.32 [40], the stereoselectivity is reversed [(—) ( ) AUC ratio of 0.90 0.06] in poor metabolizers of debrisoquine (Table 3). 

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