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Aims To investigate the transfer of escitalopram and its demethyl metabolite into milk, the absolute and relative infant doses via milk and to assess any unwanted effects in the breastfed infant. Methods Multiple samples of blood and milk were obtained over a dose interval at steady state from eight women who were taking escitalopram for postnatal depression. Drug concentrations in plasma and milk were measured by high-performance liquid chromatography and milk/plasma ratio (M/PAUC), absolute infant dose and relative infant dose were estimated by standard methods. Their breastfed infants were also examined clinically and in five infants a blood sample was taken for drug analysis. Results The median dose taken by the women was 10 mg day−1. The mean (95% confidence interval) M/PAUC was 2.2 (2.0, 2.4) for escitalopram and 2.2 (1.9, 2.5) for demethylescitalopram. Absolute infant doses were 7.6 µg kg−1 day−1 (5.2, 10.0) for escitalopram and 3.0 µg kg−1 day−1 (2.4, 3.6) for demethylescitalopram. The total relative infant dose for escitalopram plus its demethyl metabolite was 5.3% (4.2, 6.4) as escitalopram equivalents. All of the infants had met normal developmental milestones and no adverse effects were seen. Compared with average maternal plasma concentrations (24 µg l−1), the concentrations of the parent drug and its metabolite in plasma from five infants were most commonly below the limit of detection (≤3 µg l−1). Conclusion The study shows that escitalopram is safe for use during breastfeeding. Because its absolute infant dose is lower than that for an equivalent antidepressant dose of rac-citalopram, it may be preferred over rac-citalopram in treating depression in lactating women. Nevertheless, each decision to breastfeed should always be made on the basis of an individual risk:benefit analysis.

Aim Diclofenac-K has been recently launched at low oral doses in different countries for over-the-counter use. However, given the considerable first-pass metabolism of diclofenac, the degree of absorption of diclofenac-K at low doses remained to be determined. The aim of this study was to determine the bioavailability of low-dose diclofenac-K. Methods A randomized, three-way, cross-over study was performed in 10 subjects. Each received diclofenac-K, 22.5 mg via short-term i.v. infusion and orally at single doses of 12.5 mg and 25 mg. Results Mean (± SD) times to maximal plasma concentration (tmax) of diclofenac were 0.48 ± 0.28 h (12.5 mg) and 0.93 ± 0.96 h (25 mg). The absolute bioavailability of diclofenac-K after oral administration did not differ significantly in the 12.5-mg and 25-mg dose group (63.1 ± 12.6%vs. 65.1 ± 19.4%, respectively). The 90% confidence intervals for the AUC∞ and AUCt ratios for the two oral regimes were 82.6, 103.4% (point estimate 92.4%) and 86.2, 112.9% (point estimate 98.6%), respectively. These values were within the acceptance criteria for bioequivalence (80–125%). Conclusions Our data indicate that diclofenac-K is rapidly and well absorbed at low dose, and are consistent with a rapid onset of action of the drug. Abbreviations AUC, area under plasma concentraton-time curve; Cmax, peak plasma concentration; CI, confidence interval; COX, cyclooxygenase; D, dose; F, absolute bioavailability; tmax, time to reach Cmax.

Aims This study was undertaken to evaluate removal of 22-oxacalcitriol (OCT), an active and intravenously used vitamin D3 analogue with less calcaemic activity, by polysulphone haemodialyser in vivo and in vitro. We further compared the pharmacodynamic efficacy [suppression of intact parathyroid hormone (iPTH)] when given intravenously either during or at the end of the haemodialysis. Methods (i) Drug clearance by the polysulphone dialyser was measured during a single continuous infusion (5 µg) for 30 min into the arterial side of the dialyser in end-stage renal failure patients with secondary hyperparathyroidism (n = 7). (ii) The drug adsorption by the hollowfibre membrane during incubation for 30 min was measured in vitro. (iii) To evaluate efficacy, the drug was given (i.v. bolus) during or at the end of haemodialysis for 4 weeks in a cross-over fashion with a washout period of 8 weeks (n = 9). Serum Ca2+, phosphate (P) and iPTH concentrations just before the initiation of the dialysis were monitored every week. Results (i) OCT was significantly cleared by the polysulphone haemodialyser, but the clearance declined in a time-dependent manner to approach zero at 30 min. Arterial (at the place between the drug infusion site and the haemodialyser column) drug concentrations did not change during the infusion (mean = 2064 ± 233 pg ml−1). Venous (just after the dialyser) drug concentrations at 10 min after the infusion were significantly lower than those of the arterial side (mean = 784 ± 84 pg ml−1); however, they increased with time and reached those of the arterial side at 30 min. (ii) In vitro, OCT was adsorbed by the membrane. The amount of adsorption was concentration-dependent and was lower in the presence of human serum (55 ± 4% without and 23 ± 4% with serum at 600 pg ml−1 of OCT). (iii) Although serum Ca2+ and P increased and iPTH decreased by both treatment regimens (i.e. OCT administered either during or at the end of haemodialysis), these changes did not significantly differ. Mean differences (and 95% confidence interval) of Ca2+, P, and iPTH at the end of the trial were 0.03 (−0.04, 0.09) mm, 0.41 (−0.43, 1.26) mg dl−1 and 38 (−42, 88) pg ml−1, respectively. Conclusion OCT is adsorbed by polysulphone dialyser in vitro and in vivo. However, the pharmacodynamic effectiveness was largely independent of the administration regimen of OCT given either during or at the end of haemodialysis.

There is considerable unexplained interindividual variability in the methadone dose-effect relationship. The efflux pump P-glycoprotein (P-gp) regulates brain access and intestinal absorption of many drugs. Evidence suggests that methadone is a P-gp substrate in vitro, and P-gp affects methadone analgesia in animals. However the role of P-gp in human methadone disposition and pharmacodynamics is unknown. This investigation tested the hypothesis that the intestinal absorption and pharmacodynamics of oral and intravenous methadone are greater after inhibition of intestinal and brain P-gp, using the P-gp inhibitor quinidine as an in vivo probe.Two randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in healthy subjects. Pupil diameters and/or plasma concentrations of methadone and the primary metabolite EDDP were measured after 10 mg intravenous or oral methadone HCl, dosed 1 h after oral quinidine (600 mg) or placebo.Quinidine did not alter the effects of intravenous methadone. Miosis t(max) (0.3 +/- 0.3 vs 0.3 +/- 0.2 h (-0.17, 0.22)), peak (5.3 +/- 0.8 vs 5.1 +/- 1.0 mm (0.39, 0.84)) and AUC vs time (25.0 +/- 5.7 vs 26.8 +/- 7.1 mm h (-6.1, 2.5)) were unchanged (placebo vs quinidine (95% confidence interval on the difference)). Quinidine increased (P0.05) plasma methadone concentrations during the absorptive phase, decreased t(max) (2.4 +/- 0.7 vs 1.6 +/- 0.9 h (0.33, 1.2)), and increased peak miosis (3.2 +/- 1.5 vs 4.3 +/- 1.6 mm (-1.96, -0.19)) after oral methadone. The C(max) (55.6 +/- 10.3 vs 59.4 +/- 14.1 ng ml(-1) (-8.5, 0.65)) and AUC of methadone (298 +/- 46 vs 316 +/- 74 ng ml(-1) h (-54, 18)) were unchanged, as were the EDDP : methadone AUC ratios. Quinidine had no effect on the rate constant for transfer of methadone between plasma and effect compartment (k(e0)) (2.6 +/- 2.6 vs 2.5 +/- 1.4 h(-1) (-3.5, 4.2)).Quinidine increased the plasma concentrations of oral methadone in the absorptive phase and the miosis caused by methadone, suggesting that intestinal P-gp affects oral methadone absorption and hence its clinical effects. Quinidine had no effect on methadone pharmacodynamics after intravenous administration, suggesting that if quinidine is an effective inhibitor of brain P-gp, then P-gp does not appear to be a determinant of the access of methadone to the brain.