Ifenprodil metabolite

It has been supposed that Ifenprodil glucuronide derivative, detectable in large amount in rabbit plasma, is related to the pharmacological actions by ifenprodil tartrate. However, a synthesized Ifenprodil glucuronide derivative was found to have no effect on platelet aggregation and vasocontraction in vitro. These results indicate that ifenprodil itself rather than its glucuronide derivative manifested the pharmacological actions [1].

Ifenprodil (dl-erythro-4-benzyl-a-(4-hy droxyphenyl)-(3-methyl-1 -piperidine ethanol) is a vasodilator and an inhibitor of platelet aggregation. The inhibitory effect on platelet aggregation ex vivo by oral administration of ifenprodil in rabbits was manifested only after the plasma ifenprodil level had reached its peak. The ex vivo effect of ifenprodil was found to be stronger than its effect under in vitro condition. Fur thermore, significant increase in rat vertebral blood flow was not manifested until 10 min after intravenous administration of this drug. These three findings suggest the pos sibility that metabolites of ifenprodil inhibit platelet aggregation ex vivo and relax cerebral blood vessels in vivo. We found that ifenprodil was readily metabolized into an Ifenprodil glucuronide derivative which was readily detectable in significantly large amounts in rabbit plasma. Therefore, to study whether the ifenprodil glucuronide derivative manifests pharmacological actions in vivo and ex vivo, we synthesized the ifenprodil glucuronide derivative and investigated its effects on platelet aggregation and con traction of basilar artery in vitro. curonide derivative was transferred to the free-form ifenprodil by hydrolysis with e3 glucuronidase (3000 Fishman units/ml) and extracted in the same way. Ifenprodil was determined by gas chromatography mass spectrometry. Analytical conditions were as follows: column, 1 % OV-17 on Gas-chrom Q (80-100 mesh) and 0.5 mx0.3 mm i.d.; column temp., 225'C; flow rate of helium , 40 ml/min; electron energy, 70 eV; internal standard, 1,2,3,4,5,6-hexahydro-6 ,11-dim ethyl -3 [2 (4-methylphenyl) ethyl] -2 ,6 methano-3-benzazocin-8-ol; selected ions (m/z), 202 (ifenprodil) and 302 (internal standard). Since ifenprodil glucuronide derivative is presumed have a structure in which a glucuronic acid is bound to the phenolic hydroxy group of ifenprodil, this derivative was synthesized by the method of Berrang et al.. Platelet aggregation in vitro was measured by using platelet-rich plasma from citrated rabbit blood by the previously reported method. The measurement of K+-induced basilar artery contraction was carried out as previously described. Ifenprodil and the ifenprodil derivative used were solubilized in saline. Only a very small amount of free-form ifenprodil and a trace amount of a free-form metabolite of ifenprodil, probably dl-ery thro-2 [4 (4-hydroxybenzyl)-piperidino]-1 (4-hydroxyphenyl)-1-propanol, were detected in rabbit plasma after oral adminis tration of ifenprodil tartrate, but a signifi cantly large amount of ifenprodil glucuronide derivative was detected (Fig. 1). The areas under the curve (0--4 hr) of unchanged ifenprodil and ifenprodil glucuronide deriva tive concentrations in the plasma were 16.08±4.91 ng•hr-ml-' and 16.73±1.16 ,1g hr-ml-', respectively. From these results, comparison of the effects of free-form ifenprodil and synthesized glucuronide derivative on ADP and collagen-induced platelet aggregation and on K{-induced con traction of basilar artery strip were carried out. Free-form ifenprodil from 1 tiM to 100 ,uM inhibited platelet aggregation induced by ADP or collagen (Fig. 2 a, b) and also relaxed the contraction of basilar artery by K+ (Fig. 2c), but the ifenprodil glucuronide derivative had no effect on platelet aggregation and arterial contraction. These results indicate that the increased potency of ifenprodil under ex vivo and in vivo conditions and the delay in its manifestation of pharmacological actions are not due to its metabolized glu curonide derivative. In the previous report (1), we indicated that it is possible that ifenprodil at a concentration too low to have an effect on platelet aggregation in vitro may manifest an ex vivo effect by interacting with endogenous PG 12. Therefore, the present results support that ifenprodil itself manifested the pharmacological actions in vivo and ex vivo [1].

[1]. Effects of ifenprodil glucuronide derivative on platelet aggregation and vasocontraction. Jpn J Pharmacol. 1987 Jul;44(3):355-7.

C27H35NO8

501.568708658218

501.236

66516-92-5

Ifenprodil tartrate;23210-58-4

6455334

Typically exists as solid at room temperature

1.272

5

9

8

36

687

5

OC(C1C=CC(=CC=1)O[C@H]1[C@@H]([C@H]([C@@H]([C@@H](C(=O)O)O1)O)O)O)C(C)N1CCC(CC2C=CC=CC=2)CC1

GXHMRNLUBONADM-FGOGJYSLSA-N

InChI=1S/C27H35NO8/c1-16(28-13-11-18(12-14-28)15-17-5-3-2-4-6-17)21(29)19-7-9-20(10-8-19)35-27-24(32)22(30)23(31)25(36-27)26(33)34/h2-10,16,18,21-25,27,29-32H,11-15H2,1H3,(H,33,34)/t16?,21?,22-,23-,24+,25-,27+/m0/s1

(2S,3S,4S,5R,6S)-6-[4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid

Ifenprodil glucuronide; 66516-92-5; beta-D-Glucopyranosiduronic acid, 4-(1-hydroxy-2-(4-(phenylmethyl)-1-piperidinyl)propyl)phenyl; (2S,3S,4S,5R,6S)-6-[4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)