CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure.

The aims of this study were to examine the relationships between CYP2D6 genotype and metoprolol dose, S- and R-metoprolol concentrations and clinical effects in patients with systolic heart failure. Data were obtained for 52 subjects, of which 27 had 2 functional alleles (24/27, CYP2D6*1/*1), 22 had 1 functional allele (18/22, CYP2D6*1/*4) and 3 had no functional alleles (CYP2D6*4/*4). Median dose-adjusted concentrations of S-metoprolol (active) were 6.3- and 3.2-fold higher in subjects with zero or one functional allele (P=0.016 and P=0.006), respectively, compared with subjects with two functional alleles. For the R-enantiomer (inactive), these concentrations were 10.7- and 3.7-fold higher (P=0.013 and P=0.003), respectively. Despite clear gene-concentration differences, no relationships between CYP2D6 genotype and dose or clinical effects could be shown. Although the number with no functional alleles was too small (n=3) to show effects, in patients with 1 functional allele other sources of variance are likely to be obscuring differences in clinical effects.

Effect of pregnancy on the pharmacokinetics of metformin.

AIMS: To determine the effects of pregnancy on metformin pharmacokinetics. METHODS: Seven women with Type 2 diabetes mellitus taking metformin throughout pregnancy were studied on two occasions, once at 28-36 weeks gestation and once at least 8 weeks postpartum. Serum metformin concentrations were determined across a dosing interval using high-performance liquid chromatography. The areas under the serum concentration-time curve from 0 to 4 h post-dose (AUC0-4) and 0 to 8 h post-dose (AUC0-8) where possible, were compared in the pregnant and non-pregnant state. RESULTS: Metformin concentrations were lower in pregnancy in six subjects, with a mean (95% CI) AUC0-4 that was 69% (53.6, 84.8) of the postpartum value. The AUC0-4 of one subject was higher in pregnancy at 142% of the postpartum value. Overall, the mean (95% CI) AUC0-4 during pregnancy for all seven subjects was 80% (51.3, 107.8) of the postpartum value (P = 0.053, two-tailed t-test; P = 0.027, one-tailed t-test). CONCLUSION: These results are consistent with our hypothesis that the clearance of metformin increases in pregnancy as a result of enhanced renal elimination. A larger study is required to establish whether metformin dose adjustments are required in late pregnancy to maintain therapeutic effect.

Quinapril and its metabolite quinaprilat in human milk.

AIMS: To measure the milk to plasma ratio (M/P) of quinapril and its active metabolite quinaprilat in lactating mothers and to assess likely infant exposure. METHODS: A single dose of quinapril 20 mg was administered to six healthy mothers who had been breastfeeding their infants for at least 2 weeks. Blood was sampled for the measurement of quinapril and quinaprilat at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h. Milk was collected for measurement of quinapril and quinaprilat concentrations over the periods -4-0, 0-4, 4-8, 8-12, 12-18, 18-24 h. The areas under the plasma and milk concentration-time curves were estimated and an M/P ratio derived for both quinapril and quinaprilat. RESULTS: The M/P ratio for quinapril was 0.12 (95% CI 0.09,0.14). No quinapril was detected in milk after 4 h. No quinaprilat was detected in any of the milk samples. The estimated 'dose' of quinapril that would be received by the infant was 1.6% (95% CI 1.0,2.2) of the maternal dose, adjusted for respective weights. CONCLUSIONS: Quinapril appears to be 'safe' during breastfeeding according to conventional criteria, although as always, the risk:benefit ratio should be considered when it is to be given to a nursing mother.