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Abstract

Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.

R E Jonkers, R P Koopmans, E J Portier and C J van Boxtel
Journal of Pharmacology and Experimental Therapeutics March 1991, 256 (3) 959-966;
R E Jonkers
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R P Koopmans
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E J Portier
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C J van Boxtel
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Abstract

The metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 256, Issue 3
1 Mar 1991
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Abstract

Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.

R E Jonkers, R P Koopmans, E J Portier and C J van Boxtel
Journal of Pharmacology and Experimental Therapeutics March 1, 1991, 256 (3) 959-966;

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Abstract

Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.

R E Jonkers, R P Koopmans, E J Portier and C J van Boxtel
Journal of Pharmacology and Experimental Therapeutics March 1, 1991, 256 (3) 959-966;
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