The excretion of zopiclone into breast milk.

1. The excretion of zopiclone into breast milk was studied in 12 lactating women in the early postpartum period following the oral administration of a single zopiclone tablet (7.5 mg). 2. The milk/plasma AUC ratio of zopiclone was 0.51 +/- 0.09 (mean +/- s.d.). Individual mean milk/plasma concentration ratios of zopiclone showed significant interindividual variation (range 0.41-0.70). 3. A comparison of pharmacokinetic parameters in the postpartum women with those reported previously in non-pregnant women, showed significantly higher Cmax values in the lactating mothers; tmax occurred later in milk than in maternal plasma. 4. Assuming a daily milk intake of 0.15 l kg-1 and 100% absorption the average infant dose of zopiclone in milk would be 1.4% of the weight adjusted dose ingested by the mother.     

Presence of chlorprothixene and its metabolites in breast milk

Summary Chlorprothixene (CPX) and CPX sulphoxide were demonstrated in breast milk from two psychotic mothers taking 200 mg CPX daily. The milk concentrations of CPX were 120 to 260% greater than in plasma. The estimated amounts of drug administered in breast milk to one of the infants were 15 and 26 µg/day for CPX and CPX sulphoxide, respectively. Accordingly, the infant dose of the parent compound would be only 0.1% of the maternal dose/kg body weight. It is not likely that CPX or its metabolite would exert any immediate pharmacological effects in the nursing infant. However, the long term effect of low doses of neuroleptic drugs in the developing infants is not yet known.     

The excretion of rosaramicin in breast milk

The excretion of rosaramicin, a macrolide antibiotic, was studied in the breast milk of ten lactating women. Breast milk and serum samples were collected for 48 hours after a single 250-mg oral dose of rosaramicin. Mean serum half-life, apparent volume of distribution, and oral clearance were 4.4 hours, 3.41 L/kg, and 6.34 mL/min/kg, respectively. Mean milk/serum ratio was 0.12 and the total amount of drug recovered over the first ten hours was 6.25 micrograms, approximately 0.0025% of the dose. A positive correlation between breast milk volume and breast milk clearance was found, suggesting that the amount of drug received by a nursing infant will depend on the volume of milk produced by the mother. Drug-induced toxicity from the parent drug is unlikely to occur in nursing infants since the amount of rosaramicin that a nursing infant could ingest is small.     

Moclobemide excretion in human breast milk.

1. Six lactating white women, aged 24-36 years, received a single oral dose of 300 mg moclobemide, between 09.00 h and 11.00 h, 3 to 5 days after the delivery of a full term neonate. 2. Complete milk collections were obtained before, 3, 6, 9, 12 and 24 h after drug administration by means of a breast pump. Venous blood samples were drawn before, and 0.5, 1, 3, 4.5, 6, 9, 12, 24 h post-dosing. 3. Moclobemide, and its major metabolite (Ro 12-8095) were measured in milk and plasma samples using h.p.l.c. The active metabolite (Ro 12-5637) could only be detected in plasma. 4. Moclobemide and its metabolites were not detectable in 24 h plasma samples. Cmax, tmax and t1/2 for moclobemide were (mean +/- s.d.) 2.70 +/- 1.24 mg l-1, 2.03 +/- 1.19 h and 2.26 +/- 0.26 h, respectively. 5. The concentrations of moclobemide and Ro 12-8095 in milk were highest at 3 h after drug administration and the drug and metabolite were not detectable after 12 h. Ro 12-5637 was not detected in any milk sample. The percentages of the dose excreted as moclobemide and Ro 12-8095 were (mean +/- s.d.) 0.057 +/- 0.020% and 0.031 +/- 0.011%, respectively. An average 3.5 kg breast-fed neonate would therefore be exposed to only a 0.05 mg kg-1 moclobemide dose (approximately 1% of the maternal dose on the mg kg-1 basis). The low amount of moclobemide excreted into breast milk is unlikely to be hazardous to suckling infants.     

Transfer of metaclazepam and its metabolites into breast milk

Ten young women took part in this study a few days after delivery (day 3 and day 5 post partum). Lactation had developed normally but the newborn infants were not breast-fed. The study was intended to investigate whether metaclazepam (Talis), a new 1,4-benzodiazepine, and some of its metabolites were present in breast milk. Levels were measured in the plasma and milk. The levels in the milk showed that metaclazepam, N-desmethylmetaclazepam and two of its metabolites with a lactam structure could be found in small amounts. Differences in metaclazepam and N-desmethylmetaclazepam concentrations in the breast milk on days 3 and 5 post partum are discussed.     

Plasma and breast milk concentrations of dothiepin and northiaden in lactating women

Plasma and breast-milk concentrations of dothiepin and its metabolite northiaden were measured in 20 lactating women receiving the drug for post-partum depression. Samples were collected at steady-state and both compounds quantitated by HPLC. Doses of dothiepin varied from 75 mg/day to 225 mg/day. Accordingly a wide range of plasma and breast-milk concentrations of dothiepin and northiaden were determined. Most determinations were made for women receiving 150 mg/day. At this dose mean (± SD) plasma concentrations of dothiepin and northiaden were 56(±27)m?g/l and 72(±79)m?g/l respectively while breast-milk concentrations were 95(±71) m?g/l and 40(±29) m?g/l for dothiepin and northiaden respectively. The data reflect the well recognised inter-individual variability in plasma concentrations for subjects receiving the same oral dose. Similar variability was noted in breast-milk concentrations at all doses of dothiepin. Dothiepin passes into the breast-milk of lactating women receiving the drug for post-partum depression. In this respect the drug is similar to other tricyclic antidepressants. The inter-individual variability of results recorded here suggest the need to determine drug concentrations on an individual basis before reaching a decision about breastfeeding. Perceived side effects in the infant are clear criteria for cessation of breastfeeding; high levels of drug in breastmilk where the infant is unaffected, warrant monitoring in view of our inadequate knowledge regarding long term effects of these drugs.     

Lidocaine excretion in breast milk

Nursing mothers are occasionally treated with intravenous lidocaine for ventricular dysrhythmias. There have been no reports on the excretion of lidocaine into breast milk. This case documents the excretion of lidocaine into breast milk in small amounts and shows the validity of the TDx methodology used in the whole-milk lidocaine assay. We observed breast-milk concentrations of lidocaine at 40 percent of the serum levels. Clinical practitioners should be aware the lidocaine is excreted into breast milk in small amounts and the mother could probably continue to safely breast-feed her child while on parenteral lidocaine. Any adverse reactions in the nursing infant would probably be limited to an idiosyncratic or allergic reaction.     

Zolpidem excretion in breast milk

Five, lactating, healthy white women were treated with a single 20 mg tablet of zolpidem 3-4 days after the delivery of a full term baby. The drug was administered at 20.00 h, 30 min after dinner, and milk samples were collected before and 3, 13 and 16 h. Venous blood 5 ml was taken before and 1.5, 3, 13, 16 h after zolpidem administration. The apparent elimination half life, estimated from plasma zolpidem concentrations was 2.6 h. The amount of zolpidem excreted in the milk at 3 h ranged between 0.76 and 3.88 micrograms, which represented 0.004 to 0.019% of the administered dose; no detectable (below 0.5 ng/ml) zolpidem was found in the milk at subsequent sampling times. The ratio of the zolpidem concentrations in breast milk and plasma at 3 h was 0.13. The apparent breast milk clearance of zolpidem, calculated from the ratio of the total amount of zolpidem excreted in milk to its AUC in plasma was 1.48 ml/h. The results show that the excretion of zolpidem in human milk is very low (below 0.02%) and that most of it takes place during the first 3 h following drug intake.     

Comparative pharmacology of dothiepin,its metabolites,and other antidepressant drugs

The pharmacology of dothiepin and its human metabolites, northiaden, dothiepin sulfoxide, and northiaden sulfoxide, has been studied to determine whether the latter contribute to the therapeutic or side effects profile of the parent tricyclic antidepressant. In vitro, dothiepin was a potent noradrenaline and 5-hydroxytryptamine (5-HT) uptake inhibitor, while its secondary amine metabolite, northiaden, was selective for noradrenaline. However, the sulfoxide metabolites were almost inactive as uptake inhibitors. Dothiepin and northiaden prevented the ptosis produced by tetrabenazine in mice and reserpine in rats and increased the mobility of mice in the Porsolt test. After repeated administration, both drugs decreased β-adrenoceptor number and stimulation of the receptor-linked adenylate cyclase by noradrenaline. Dothiepin had a higher affinity than northiaden for histamine H₁, muscarinic and various adrenergic and 5-HT receptors in vitro, whereas the sulfoxide metabolites were inactive. Overall, the data indicate northiaden almost certainly contributes to the therapeutic actions of dothiepin, but the sulfoxide metabolites do not. However, the latter are also unlikely to produce any side effects. A comparison of dothiepin with other tricyclics revealed important divergences in the profiles of uptake inhibition and receptor affinity. Thus, dothiepin is generally similar to imipramine in its pharmacology, but it differs considerably from amitriptyline and doxepin. © 1992 Wiley-Liss, Inc.     

Amitriptyline and nortriptyline excretion in human breast milk

Simultaneous blood and milk samples were obtained from a 30-year-old woman who was on sustained release amitriptyline, and the concentrations of amitriptyline and the active metabolite, nortriptyline, were estimated by GLC. Serum and milk concentrations were similar with a slight tendency for the amitriptyline concentrations to be higher in milk. Calculation of the transfer of drug from the mother to the baby showed that the baby received an amitriptyline dose which was about one hundredth the dose given to the mother. No active drug could be estimated in the baby's serum and the baby showed no clinical signs which could be drug related.     

Biliary excretion of nitrazepam and its metabolites in rats

A single intravenous administration of nitrasepam (10 mg/kg) resulted in its excretion as free and conjugated metabolites in the bile of albino rats. The initial compounds, amino- and acetamido derivatives were deteced among free metabolits. Conjugated forms were recovered as N-glucoronides (5-nitro-2-aminobenzophenon and amine) and as O-glucoronides (C3-hydroxylated derivatives of nitrasepam and of acetamide). The presence of a considerable amount of nitrasepam and of its metabolites in the rats' bile is suggestive of their enterohepatic circulation.