Thomas Eschenhagen

Objective: The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance. Cytochrome P450 2D6 (CYP2D6) poor metabolizers exhibit 3‐ to 10‐fold higher plasma concentrations after administration of metoprolol than extensive metabolizers. However, the impact of the CYP2D6 genotype on the occurrence of adverse effects of metoprolol remains controversial. This study addressed whether the incidence of poor metabolizers was higher in patients with metoprolol‐associated adverse effects than in the German population at large.Methods: Approximately 1200 German physicians were asked to report on patients who had experienced pronounced adverse effects in association with administration of metoprolol. CYP2D6 genotypes were determined with a combination of allele‐specific polymerase chain reaction and polymerase chain reaction‐restriction fragment length polymorphism. The adverse effects, consisting of symptoms related to β‐adrenergic receptor blockade and nonspecific symptoms, were recorded by use of a standardized questionnaire.Results: Twenty‐four patients were included in the study. Nine patients had 2 null alleles (poor metabolizer genotype; 38%); the remaining 15 had either 1 null allele (n = 7) or no null alleles (n = 8). Therefore the occurrences of poor metabolizer genotypes in the study population were 4.9‐ and 5.2‐fold more frequent, respectively, than that found in unselected members of the German population in two large studies (P < .0001; χ² test).Conclusions: These data showed that CYP2D6 poor metabolizers had a 5‐fold higher risk for development of adverse effects during metoprolol treatment than patients who were not poor metabolizers. Because the absolute risk of adverse effects of metoprolol is unknown, the clinical relevance of the CYP2D6 genotype for metoprolol therapy has to be determined in a prospective manner.Clinical Pharmacology & Therapeutics (2002) 72, 429–437; doi: 10.1067/mcp.2002.127111

A technique is presented that allows neonatal rat cardiac myocytes to form spontaneously and coherently beating 3-dimensional engineered heart tissue (EHT) in vitro, either as a plane biconcaval matrix anchored at both sides on Velcro-coated silicone tubes or as a ring. Contractile activity was monitored in standard organ baths or continuously in a CO₂ incubator for up to 18 days (=26 days after casting). Long-term measurements showed an increase in force between days 8 and 18 after casting and stable forces thereafter. At day 10, the twitch amplitude (TA) of electrically paced EHTs (average length × width × thickness, 11 × 6 × 0.4 mm) was 0.51 mN at length of maximal force development (L_max) and a maximally effective calcium concentration. EHTs showed typical features of neonatal rat heart: a positive force–length and a negative force–frequency relation, high sensitivity to calcium (EC₅₀ 0.24 mM), modest positive inotropic (increase in TA by 46%) and pronounced positive lusitropic effect of isoprenaline (decrease in twitch duration by 21%). Both effects of isoprenaline were sensitive to the muscarinic receptor agonist carbachol in a pertussis toxin-sensitive manner. Adenovirus-mediated gene transfer of β-galactosidase into EHTs reached 100% efficiency. In summary, EHTs retain many of the physiological characteristics of rat cardiac tissue and allow efficient gene transfer with subsequent force measurement. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng 68: 106–114, 2000.