The study focuses on its effects on liver haemoproteins, including cytochrome P-450, catalase, and 5-aminolevulinic acid synthetase. It is metabolized by the cytochrome P-450 drug-metabolizing system, and this metabolism is thought to be necessary for its effects on haem breakdown. [1]

According to studies, allyl isopropyl acetamide induces a noticeable green pigmentation in the liver in addition to increasing the amount of porphyrins in animal urine and liver. After receiving high dosages of allylisopropyl acetamide over an extended period of time, the rats showed good recovery and their measured parameters returned to normal. Rats may tolerate and recover from the harm produced by long-term allyl isopropyl acetamide treatment [1]. Aprons have been linked to recorded cases of mucocutaneous ocular syndrome and fixed medication eruptions [2].

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In a study on male Sandoz OFA-SPF rats, Apronalide was administered subcutaneously at a daily dose of 400 mg/kg for 21 days. This was followed by a 21-day recovery period. The treated animals gained weight normally and showed no outward signs of treatment. [1]
The administration of Apronalide led to several significant changes in the liver:
- A marked decrease in catalase activity, reaching near-zero levels by day 10, which was maintained until treatment cessation. During recovery, catalase activity rebounded, exceeding control levels by nearly 100% before declining.
- A fluctuating effect on cytochrome P-450 concentration, which decreased initially, returned to control levels by day 7, then declined again to a minimum by day 17. Recovery to control levels was not reached until day 42.
- Cytochrome b5 concentration was only marginally affected, oscillating around control values.
- 5-Aminolevulinate synthetase activity increased sharply, peaking around day 17, and returned to control levels by day 30 during recovery.
- Urinary coproporphyrin excretion increased ten-fold, peaking sharply at day 17, then rapidly decreased. Uroporphyrin levels rose after treatment ceased, peaking at day 27 before returning to normal. [1]
Microsomal preparations from the livers, lungs, and kidneys of treated rats showed a marked green pigmentation, which was absent in controls. This pigmentation was lost during the recovery period. [1]
Serum parameters indicative of cell damage (glutamate-pyruvate transaminase, glutamate-oxalacetate transaminase, alkaline phosphatase, and bilirubin) showed a significant increase between days 10 and 18, returning to normal thereafter. Liver weights increased during treatment but returned to control ranges by day 31 of recovery. [1]

Several enzyme assays were performed on liver homogenates and subcellular fractions from control and treated rats.
Catalase activity was determined in whole liver homogenate using the method of Beers & Sizer (1952).
Cytochromes P-450 and b5 were measured in the microsomal fraction using the procedure outlined by Omura & Sato (1964).
5-Aminolevulinate synthetase was determined in whole homogenate using the methods of Marver et al. (1966a) and Granick (1966).
Serum enzymes, including glutamate-pyruvate transaminase, glutamate-oxalacetate transaminase, and alkaline phosphatase, were determined using standard autoanalyzer methods (Bergmeyer & Bernt, 1974; Walter & Schuett, 1974). [1]

The study used 84 male Sandoz OFA-SPF rats, initially weighing 140-150 g. Apronalide was suspended in propandiol at a concentration of 50 mg/ml. The drug was administered in two equal daily subcutaneous injections, 8 hours apart, for a total daily dose of 400 mg/kg. This dosing regimen continued for 21 days. Control rats were treated similarly with propandiol only. A recovery period of 21 days followed the treatment phase. Groups of three rats from both the treated and control groups were sacrificed at days 1, 3, 7, 10, 14, 17, and 21 of treatment, and at corresponding times during the 21-day recovery period. Animals were sacrificed by cervical dislocation. Livers were perfused, homogenized, and used for biochemical analyses. Urine samples were collected in 24-hour periods throughout the study and stored frozen for porphyrin analysis. [1]

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The study used 84 male Sandoz OFA-SPF rats, initially weighing 140-150 g. Apronalide was suspended in propandiol at a concentration of 50 mg/ml. The drug was administered in two equal daily subcutaneous injections, 8 hours apart, for a total daily dose of 400 mg/kg. This dosing regimen continued for 21 days. Control rats were treated similarly with propandiol only. A recovery period of 21 days followed the treatment phase. Groups of three rats from both the treated and control groups were sacrificed at days 1, 3, 7, 10, 14, 17, and 21 of treatment, and at corresponding times during the 21-day recovery period. Animals were sacrificed by cervical dislocation. Livers were perfused, homogenized, and used for biochemical analyses. Urine samples were collected in 24-hour periods throughout the study and stored frozen for porphyrin analysis. [1]

Apronalide was administered subcutaneously. It is metabolized, likely by the cytochrome P-450 system, forming an active metabolite (postulated to be an epoxide on the allyl group). Pigmentation was observed in the microsomes of the liver, lung, and kidney, suggesting distribution to these organs. No specific PK parameters (half-life, bioavailability, etc.) are provided. [1]

Apronalide is described as a porphyrogenic agent. Its administration at 400 mg/kg/day for 21 days caused significant but reversible toxic effects in rats. These included liver cell damage (indicated by elevated serum transaminases and alkaline phosphatase), disruption of haem biosynthesis and degradation pathways (indicated by altered enzyme activities and urinary porphyrin excretion), and a marked green pigmentation of the liver, lung, and kidney microsomes. Despite these effects, the treated animals gained weight normally, and all measured parameters returned to normal during the 21-day recovery period, demonstrating that the induced lesions are reversible. The increase in serum enzymes between days 10 and 18 indicates a period of cytotoxic potential. The study suggests that the toxicity is linked to the metabolism of Apronalide by cytochrome P-450, producing a reactive metabolite that causes haem breakdown. [1]

[1]. The effect of prolonged administration of allylisopropylacetylurea to rats on cytochrome P-450 and other liver haemoproteins. Xenobiotica. 1976 Mar;6(3):151-7.

[2]. Fixed drug eruption due to allylisopropylacetylurea. Contact Dermatitis. 1993 May;28(5):282-4.

Apronal is an N-acylurea drug. Apronal was approved for marketing in Japan. However, it has been withdrawn from the market in many other countries due to the occurrence of thrombocytopenic purpura in patients.

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Apronalide (also known as Sedormid®) is a compound containing an allyl group. It is closely related to allylisopropylacetamide. Previous studies showed that it increases porphyrins in the liver and urine and causes a green pigmentation of the liver. This study investigates the effects of its long-term administration in rats, focusing on liver haemoproteins and the reversibility of these effects. The proposed mechanism of action involves metabolism of Apronalide by cytochrome P-450 to a reactive metabolite (likely an epoxide). This metabolite then interacts with haem, causing its breakdown. The destruction of haem disrupts the negative feedback control of the haem biosynthetic pathway, leading to an induction of 5-aminolevulinate synthetase and resulting in porphyria. The green pigment is thought to be a breakdown product of haem, not an accumulation of precursors. The study concludes that rats can tolerate and recover from long-term administration of high doses of Apronalide. [1]

C9H16N2O2

184.24

184.121

528-92-7

10715

White to off-white solid powder

1.025g/cm3

196 °C

1.474

2.12

2

2

4

13

212

0

KSUUMAWCGDNLFK-UHFFFAOYSA-N

InChI=1S/C9H16N2O2/c1-4-5-7(6(2)3)8(12)11-9(10)13/h4,6-7H,1,5H2,2-3H3,(H3,10,11,12,13)

N-carbamoyl-2-propan-2-ylpent-4-enamide

ApronalApronalideIsodormidSedormidAllylisopropylacetylurea

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)

DMSO : ~150 mg/mL (~814.16 mM)

Solubility in Formulation 1: ≥ 3.75 mg/mL (20.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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