Metoprolol metabolism

Lennard MS, Iyun AO, Jackson PR, Tucker GT, Woods HF. Evidence for a dissociation in the control of sparteine, debrisoquine and metoprolol metabolism in Nigerians. Pharmacogenetics 1992 2 89-92. 

Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF. Oxidation phenotype—a major determinant of metoprolol metabolism and response. N Engl J Med 1982 307 1558-1560. 

Metoprolol is a (3-blocker that has been proposed as a pharmacokinetic alternative to debrisoquine in countries where it is difficult to use debrisoquine. Metoprolol is metabolized to desmethylmetroprolol and a-hydroxymetoprolol by CYP2D6 (124). The a-hydroxymetoprolol metabolite has been shown to be bimodally distributed and to correlate with the debrisoquine oxidation phenotype (125). Again, metoprolol has been used primarily to distinguish between CYP2D6 EMs and PMs. However, in African populations, the metoprolol metabolic ratio failed to predict the PMs of debrisoquine (126). These studies would suggest that in some ethnic groups metoprolol may not be a suitable probe. 

McGourty JC, Silas JH, Lennard MS, et al. Metoprolol metabolism and debrisoquine oxidation polymorphism-population and family studies. Br J Clin Pharmacol 1985 20 555-566. 

Johnson JA, Burlew BS. Metoprolol metabolism via cytochrome P4502D6 in ethnic populations. Drug Me tab Dispos 1996 24 350-5. 

Genetic differences can also influence the likelihood of some drug interactions. For example, coadministration of the antiarrhythmic propafenone to patients being treated with metoprolol substantially reduces metoprolol metabolic clearance in extensive... 

U. Werner, N. Feifel, and T. Eschenhagen (2002). Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 12, 465 72. 

Lancaster DL, Adio RA, Tai KK, Simooya 00, Broadhead GD, Tucker GT, Lennard MS. Inhibition of metoprolol metabolism by chloroquine and other antimalarial drugs. JPharm Pharmacol (1990) 42, 267-71. 

Fluoxetine and paroxetine inhibit the cytochrome P450 isoenzyme CYP2D6 thus inhibiting the metabolism of some beta blockers (e.g. propranolol, metoprolol, carvedilol) so that they accumulate, the result being that their effects, such as bradycardia, may be increased. Citalopram and escitalopram may also inhibit CYP2D6. In vitro studies with human liver microsomes found that fluoxetine and paroxetine are potent inhibitors of metoprolol metabolism and fluvoxamine, sertraline and citalopram less potent. However, fluvoxamine also potently inhibits the metabolism of propranolol by CYP1A2. Beta blockers that are not extensively me-... 

The absorption of metoprolol after po dosing is rapid and complete. The dmg undergoes extensive first-pass metabolism in the liver and only 50% of the po dose in bioavailable. About 12% of the plasma concentration is bound to albumin. The elimination half-life is 3—7 h and less than 5% of the po dose is excreted unchanged in the urine. The excretion of the dmg does not appear to be altered in patients having renal disease (98,99,108). 

Both metoprolol and carvedilol are metabolized by the liver through cytochrome P-450 (CYP450)2D6 and undergo extensive first-pass metabolism. Bisoprolol is not as commonly used since it is not Food and Drug Administration (FDA)-approved for this use. 

The answer is b. (Hardmanr p 906.) Cimetidine reversibly inhibits cytochrome P450. This is important in phase I bio transformation reactions and inhibits the metabolism of such drugs as warfarin, phenytoin, propranolol, metoprolol, quinidine, and theophylline. None of the other enzymes are significantly affected. 

There are pharmacokinetic differences among /1-blockers in first-pass metabolism, serum half-lives, degree of lipophilicity, and route of elimination. Propranolol and metoprolol undergo extensive first-pass metabolism. Atenolol and nadolol have relatively long half-lives and are excreted renally the dosage may need to be reduced in patients with moderate to severe renal insufficiency. Even though the half-lives of the other /J-blockers are much shorter, once-daily administration still may be effective. /J-Blockers vary in their lipophilic properties and thus CNS penetration. 

All these compounds are moderately lipophilic and should show excellent ability to cross biological membranes by transcellular absorption. Propranolol, betaxolol and metoprolol all have minimal gut first-pass metabolism, as shown by the low value for E(g. i.). Metabolism and first pass effects for these compounds are largely confirmed to the liver as shown by the values for E(g. i.). In contrast talinolol shows high extraction by the gastrointestinal tract with low liver extraction [13]. These effects are illustrated graphically in Figure 3.9 which shows the bioavailability predicted from hepatic extraction contrasted with that seen in vivo in man. 

Andersson B, Lomsky M, Waagstein F. The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure. A study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol. Eur. Heart J. 1993 14 1375-85. 

In vitro, diphenhydramine inhibits CYP2D6 and therefore may interact with beta-blockers, some antidepressants such as desipramine, and antipsychotics such as promethazine. In a study by Hamelin et al. (2000), diphenhydramine was found to inhibit the metabolism of metoprolol in phenotypically extensive metabolizers, but not in poor metabolizers. The effects where observed clinically as well as pharma-cokinetically. 

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

Atenolol is not extensively metabolized and is excreted primarily in the urine with a half-life of 6 hours it is usually dosed once daily. Recent studies have found atenolol less effective than metoprolol in preventing the complications of hypertension. A possible reason for this difference is that once-daily dosing does not maintain adequate blood levels of atenolol. The usual dosage is 50-100 mg/d. Patients with reduced renal function should receive lower doses. 

There are other examples in which chirality is a factor in determining which particular metabolic route occurs, such as the metabolism of the drugs propranolol, metoprolol, and warfarin. 

Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, Raskin P, Wright JT, Oakes R, Lukas MA, Anderson KM, Bell DSH, for the GEMINI Investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension. A randomized controlled trial. JAMA 2004 292 2227-36. 

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