In vitro, in human liver microsome preparations, it has been shown that no significant amount of desmopressin is metabolised in the liver and thus human liver metabolism in vivo is not likely to occur.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今日，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今日2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Following nasal spray administration of 0.83 mcg and 1.66 mcg, median time to peak plasma concentrations (Tmax) was 0.25 and 0.75 hour, respectively. The peak plasma concentration was approximately 4.00 (± 3.85) pg/mL and 9.11 (± 6.90) pg/mL, respectively. The bioavailability of 1.5 mg/mL desmopressin administered by the intranasal route was between 3.3 and 4.1%. The absolute bioavailability of orally administered desmopressin varies between 0.08% and 0.16% where the mean maximum plasma concentration is reached within 2 hours.
Desmopressin is mainly excreted in the urine. About 65% of the amount of desmopressin absorbed after oral administration could be recovered in the urine within 24 hours.
Purpose. To prepare and characterize a reversibly lipidized dipalmitoyl desmopressin (DPP), and to compare its anti-diuretic efficacy and biodistribution with that of unmodified desmopressin (DDAVP).Methods. Dithiothreitol (DTT) was used to reduce the intramolecular disulfide bond in DDAVP, and the reduced DDAVP was treated with a thiopyridine-containing disulfide lipidization reagent, Pal-CPD. The product, DPP, was purified by acid precipitation and, subsequently, by size-exclusion chromatography. Reversed-phase HPLC was used to analyze the purity and to evaluate the hydrophobicity of the product. Mass spectrometry was employed to characterize its molecular structure. The biological activity of DPP was demonstrated by the antidiuretic effects in vasopressin-deficient Brattleboro rats. Preliminary pharmacokinetic and biodistribution studies of intravenously injected DDAVP and DPP were carried out in CF-1 mice.Results. DDAVP was readily reduced by a 2-fold molar excess of DTT at 37 degrees C for 0.5 hr. DPP was formed by the reaction of reduced DDAVP with Pal-CPD. Each DPP molecule contains two palmitic acid moieties, which link to the peptide via two disulfide bonds. After acid precipitation and size-exclusion chromatography, the purity was found to be approximately 95%, and the overall yield was 57%. When DPP was administered subcutaneously to Brattleboro rats, the potency of the anti-diuretic activity of DDAVP was enhanced to more than 250-fold. The plasma concentration of intravenously injected DDAVP in mice decreased rapidly during the first 20 min and followed by a slow elimination rate. However, in DPP administered mice, the plasma concentration actually increased in the first 20 min, followed by a slow elimination with a rate similar to that in DDAVP-injected mice. The regeneration of DDAVP was detected in the plasma of mice treated with DPP. Studies of the organ distribution in mice indicated that the liver retention of DPP was longer than that of DDAVP. On the other hand, the intestinal excretion of DPP was significantly less than that of DDAVP.Conclusions. The 250-fold increase of the anti-diuretic potency in DPP is most likely due to a slow elimination and prolonged tissue retention, together with the regeneration of active DDAVP, in the animals. Our results indicate that reversible lipidization is a simple and effective approach for improving the efficacy of many peptide drugs.
This invention provides novel compounds according to general formula (1) wherein A is a bicyclic or tricyclic azepine derivative, V
1
and V
2
are both H, OMe or F, or one of V
1
and V
2
is Br, Cl, F, OH, OMe, OBn, OPh, O-acyl, N
3
, NH
2
, NHBn or NH-acyl and the other is H, or V
1
and V
2
together are ═O, —O(CH
2
)
p
O— or —S(CH
2
)S—; W
1
is either O or S; X
1
and X
2
are both H, or together are ═O or ═S; Y is OR
5
or NR
6
R
7
; R
1
, R
2
, R
3
and R
4
are independently selected from H, lower alkyl, lower alkyloxy, F, Cl and Br; R
5
is selected from H and lower alkyl; R
6
and R
7
are independently selected from H and lower alkyl, or together are —(CH
2
)
n
—; n=3, 4, 5, 6; and p is 2 or 3. The compounds are agonists at the vasopressin V2 receptor and are useful as antidiuretics and procoagulants. The invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.
The invention relates to a pharmaceutical or nutraceutical formulation comprising a core, comprising an active pharmaceutical or nutraceutical ingredient, a penetration promoter and a bioavailability promoting agent, and a polymeric coating for the gastrointestinal targeted release of the active ingredient, characterized in that the bioavailability promoting agent is a pharmaceutically acceptable inhibitor of proteolytic enzymes, which increases the oral bioavailability of the active ingredient by a factor of at least five, compared to a corresponding formulation without the bioavailability promoting agent.
The invention relates to a pharmaceutical or nutraceutical formulation comprising a core, comprising an active pharmaceutical or nutraceutical ingredient, a penetration promoter and a bioavailability promoting agent, and a polymeric coating for the gastrointestinal targeted release of the active ingredient, characterized in that the bioavailability promoting agent is a pharmaceutically acceptable inhibitor of proteolytic enzymes, which increases the oral bioavailability of the active ingredient by a factor of at least five, compared to a corresponding formulation without the bioavailability promoting agent.
Provided herein are processes for carrying out a chemical reaction of a substrate in a diluted reaction mixture. The processes include conducting the reaction mixture having reaction product and solvent to a filtration membrane which is permeable to the solvent but impermeable to the reaction product. Solvent which permeates the filtration membrane for dilution of the substrate feed is recycled.
Vasopressin-2 receptor agonists, pharmaceutical compositions thereof and methods for using the foregoing for treating diabetes insipidus, primary nocturnal enuresis, and nocturia.
