title: Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.
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)
authors.affiliation: Department of Medicine and Pharmacology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: R E
authors.initials: RE
authors.lastname: Jonkers
authors.forename: R P
authors.initials: RP
authors.lastname: Koopmans
authors.forename: E J
authors.initials: EJ
authors.lastname: Portier
authors.forename: C J
authors.initials: CJ
authors.lastname: van Boxtel
mesh_terms: D000284:Administration, Oral; D000328:Adult; D003647:Debrisoquin / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D010641:Phenotype; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D013237:Stereoisomerism; D013726:Terbutaline / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D011943:Receptors, Adrenergic, beta; D008790:Metoprolol; D013726:Terbutaline; D003647:Debrisoquin