Dosulepin undergoes extensive hepatic metabolism, to form main metabolites N-demethylated derivative northiaden (desmethyldosulepin or northiaden) and dosulepin S-oxide. Northiaden S-oxide is among 12 basic metabolites that are found in urine. The metabolic pathways of dosulepin is thought to involve N-demethylation, S-oxidation and glucuronic acid conjugation.
Dothiepin-X-oxide is the major metabolite. Northiaden (desmethyl-dothiepin) is an N-demethylated derivative. Both metabolites have antidepressant activity.
Twenty-seven healthy men received three single oral doses of 50-, 100-, and 150-mg dothiepin hydrochloride capsules in a three-way randomized, crossover dose-proportionality study. ... Plasma concentration-time profiles of the three major metabolites of dothiepin, the S-oxide derivative of dothiepin, N,N-dimethyl[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (2), the demethyl derivative, N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine (3) and the demethyl S-oxide derivative N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (4), were described by a one-compartment model with apparent first-order formation. The AUC infinity values of the S-oxide 2 and the demethyl S-oxide 4 increased proportionally with dose. The dose proportionality of the demethyl metabolite 3 may not be ascertained from the data in this study. The corresponding half-lives of the three metabolites, which are dose independent, were approximately 24, 28, and 40 hr, respectively. /Dothiepin Hydrochloride/
Only small amounts of unconjugated dothiepin (unchanged drug) and northiaden were excreted in urine over a 72 hr period. More than 10% of the dose was excreted as conjugated dothiepin and less than 0.8% of the dose as conjugated northiaden. Conjugated dothiepin was thus found to be an important metabolite of dothiepin. Conjugated dothiepin and northiaden were hydrolyzed with beta-glucuronidase, and their hydrolysis inhibited with 1,4 saccharolactone. Conjugated dothiepin and northiaden were found to be a quaternary ammonium-linked glucuronide and a tertiary N-glucuronide, respectively.
... Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S-oxide, two metabolites of dothiepin, were measured. Dothiepin S-oxide was the major metabolic reaching a peak level of 81 (34-150) ug/l at 5 (4-6) hr. In comparison, northiaden reached a peak concentration of only 10 (3-21) ug/l at 5 (4-9) hr. The mean half-life of elimination of dothiepin S-oxide was 19 (13-35) hr while that for northiaden was 33 (22-60) hr.
◉ Summary of Use during Lactation:Dothiepin is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. Limited information indicates that maternal doses of up to 225 mg daily produce low levels in milk and breastfed infants' serum, and cause no adverse developmental consequences. Dothiepin would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.
◉ Effects in Breastfed Infants:Eight women who were receiving dothiepin for depression breastfed (extent not stated) their infants aged 0.13 to 12.5 months of age. Maternal dosages ranged from 25 to 225 mg daily (0.38 to 4.5 mg/kg daily). None of the infants had any noticeable adverse reactions.
A retrospective, case-control study of 15 women who breastfed while taking dothiepin for depression compared the neurocognitive outcomes of their infants to those in a group of 15 depressed mothers who had not taken an antidepressant during breastfeeding and another 36 women without depression. The mothers in the dothiepin group had taken dosages of 150 to 225 mg daily for 4 to 134 weeks during breastfeeding. Infants had been exposed to dothiepin in breast milk at times from 3 to 152 weeks of age and were assessed at 3 to 5 years of age. There was no evidence of negative effects on the infants' development using a number of rating scales.
Two infants were breastfed for 7 to 18 weeks during maternal use of dothiepin. The drug was started when both infants were 8 weeks of age. One mother started with a dose of 50 mg daily that was increased to 100 mg daily; she took dothiepin for 33 weeks during breastfeeding. The other mother was taking 225 mg daily and nursed her infant for 25 weeks during breastfeeding. Formal testing indicated no adverse effects on infant development up to 30 months of age.
◉ Effects on Lactation and Breastmilk:Galactorrhea has been reported in one woman taking dothiepin.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking dothiepin.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
来源:Drugs and Lactation Database (LactMed)
毒理性
相互作用
癫痫或心律失常可能会在服用大量循环性抗抑郁药的患者中由氟马西尼诱发。/氟马西尼/
Seizures or arrhythmias may be precipitated /SRP: by flumazenil/ in patients with a serious cyclic antidepressant overdose. /Flumazenil/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
蛋白质的高度结合以及广泛的分布体积，往往排除了血液透析和血液灌流的潜在有用性。
The high degree of protein binding, together with the extensive volume of distribution, tends to preclude the potential usefulness of hemodialysis and hemoperfusion.
Following a dothiepin overdose leading to ventricular fibrillation and cardiac arrest, an adult was treated with intravenous sodium bicarbonate, dopamine, and lidocaine with hyperventilation. His condition remained unstable. One hour later, intravenous sodium chloride ... was given over 5 minutes. The blood pressure rose immediately; the QRS complexes narrowed and cardiac abnormalities became less frequent. Similar episodes of hypotension and cardiac abnormalities over the following days were reversed by rapid infusion of sodium chloride.
Treatment consists largely of gastric lavage and activated charcoal (either single or multiple doses). Although use of activated charcoal suggests a role in decreasing the half-life of dothiepin, other studies with TCAs show little or no such significant decrease in half-life.
Dosulepin is well absorbed from the intestines to reach the peak plasma concentration of 37.6ng/mL at 2.18 hours (Tmax) following oral administration of 25mg. The steady state concentrations are variable among individuals due to dynamic relationship between the drug dose and plasma concentration.
Dosulepin is predominantly cleared via renal elimination, mainly in the form of metabolites. Renal excretion of dosulepin and its metabolites accounts for 50% - 60% of total elimination, and biliary/fecal excretion is about 15%-40%.
The mean apparent Vd is approximately 45 L/kg after oral administration of 75mg dosulepin. It crosses the blood-brain barrier to mediate its antidepressant actions and also crosses the placental barriers, with low concentration of the drug excreted in breast milk.
来源:DrugBank
吸收、分配和排泄
清除
口腔清除率大约为1.36升/千克
Oral clearance is approximately 1.36 L/kg
来源:DrugBank
吸收、分配和排泄
多塞平及其代谢物已在母乳中被检测到。婴儿每天的总平均暴露量大约占母亲多塞平剂量的4.4%。
Dothiepin and its metabolites have been detected in breast milk. The mean total daily infant exposure amounts to about 4.4% of the maternal dothiepin dosage.
The photochemical stability of <i>cis-</i> and <i>trans</i>- isomers of tricyclic neuroleptic drugs
作者：A Li wan Po、W J Irwin
DOI：10.1111/j.2042-7158.1980.tb12839.x
日期：2011.4.12
Abstract
The irradiation of the tranquillizers flupenthixol, clopenthixol and chlorprothixene has been found to induce rapid cis-trans isomerization. The composition of the photostationary mixture is not that of the batch drug and hence this process may affect the activity. Further decomposition to a thioxanthone derivative occurs rapidly in the presence of air. Exclusion of oxygen, however, does not prevent further degradation and a slower secondary isomerization is observed on prolonged irradiation. Doxepin and dothiepin also undergo analogous reactions but the isomerizations are much slower and the oxidative degradation yields many products.
