Peringatan Keamanan

Patients experiencing an overdose may present with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia.Label These symptoms may rapidly resolve.Label Generally no treatment is required for these overdoses.A179113

The oral lowest dose causing toxic effect (TDLO) for children is 30mg/kg/21W, oral TDLO for men is 24mg/kg/4W, oral TDLO for women is 56mg/kg/8W.L6592 The intraperitoneal LD50 for rats is 901mg/kg, oral LD50 for mice is 3389mg/kg, oral LD50 for rats is >4000mg/kg.L6592

Isotretinoin is associated with major congenital malformations, spontaneous abortion, and premature birth.Label It is unknown if isotretinoin is expressed in breast milk but due to the associated hazards a decision should be made to either stop nursing or stop taking isotretinoin.Label

In animal studies, isotretinoin was associated with an increased risk of pheochromocytoma and adrenal medullary hyperplasia at doses above the recommended clinical dose.Label Isotretinoin was negative for the Ames test of mutagenicity once and weakly positive a second time.Label It has not been shown to be clastogenic.Label A study in dogs noted testicular atrophy after doses of 10-30 times the recommended clinical dose for 30 weeks.Label In trials with men there were no effects seen on sperm count, motility, morphology, ejaculate volume, and seminal plasma fructose.Label

Isotretinoin

DB00982

small molecule approved

Deskripsi

Isotretinoin is a retinoid derivative of vitamin A used in the treatment of severe recalcitrant acne.Label It was most widely marketed under the brand name Accutane, which has since been discontinued.L6574 Isotretinoin is associated with major risks in pregnancy and is therefore only available under the iPLEDGE program in the United States.L6579 The first isotretinoin-containing product was FDA approved on 7 May 1982.L6574

Struktur Molekul 2D

Berat 300.4351
Wujud solid

Peta Jejaring Molekuler
Legenda: ObatTargetGenEnzim(Panah → menunjukkan arah efek / relasi)TransporterCarrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half life ranges from 7-39 hours[L6589] with a mean elimination half life of 20 hours.[A179089] The half life of 4-oxo-13-cis-retinoic acid ranges from 17-50 hours with a mean elimination half life of 25 hours.[L6589]
Volume Distribusi The volume of distribution in humans is unknown because there is no intravenous preparation.[L6589] In a study of pediatric patients with neuroblastoma the volume of distribution was found to be 85L.[A179107] The volume of distribution was also found to be 2432mL/kg in guinea pigs and 1716mL/kg in obese rats.[A179104]
Klirens (Clearance) The clearance of isotretinoin is 15.9L/h in pediatric patients with neuroblastoma.[A179107] Clearance is also 21.3mL/min/kg in guinea pigs and 7.2mL/min/kg in obese rats.[A179104]

Absorpsi

Patients reach a maximum concentration of 74-511ng/mL after 1-4 hours following a 100mg oral dose.A179089 Isotretinoin is better absorbed with a high fat meal and bioavailability may change from one brand to another.Label Following a 40mg oral dose, fasted subjects reached a maximum concentration of 314ng/mL in 2.9 hours with an area under the curve of 4055ng/mL\*hr.Label Subjects given a high fat meal and a 40mg oral doses reached a maximum concentration of 395ng/mL in 6.4 hours with an area under the curve of 6095ng/mL\*mL.Label

Metabolisme

Isotretinoin, or 13-cis-retinoic acid can undergo reversible cis-trans isomerization to all-trans-retinoic acid.A179116 Isotretinoin undergoes 4-hydroxylation to 4-hydroxy-13-cis-retinoic acid, which is oxidized to the main metabolite 4-oxo-13-cis-retinoic acid.A179116,A179101. All-trans-retinoic acid undergoes 4-hydroxylation to 4-hydroxy-all-trans-retinoic acid, which is oxidized to 4-oxo-all-trans-retinoic acid.A179116 4-oxo-13-cis-retinoic acid can undergo reversible cis-trans isomerization to 4-oxo-all-trans-retinoic acid.A179116

Rute Eliminasi

Isotretinoin and its metabolites are conjugated and excreted in the urine and feces in similar amounts.Label 53-74% of an oral dose is eliminated as unchanged isotretinoin in the feces.A179089

Interaksi Makanan

3 Data
  • 1. Avoid alcohol. Alcohol with isotretinoin can lead to inflammation of the liver.
  • 2. Avoid vitamin A supplements.
  • 3. Take with food. High-fat food increases drug absorption.

Interaksi Obat

909 Data
Mipomersen Isotretinoin may increase the hepatotoxic activities of Mipomersen.
Diethylstilbestrol The therapeutic efficacy of Diethylstilbestrol can be decreased when used in combination with Isotretinoin.
Ethinylestradiol The therapeutic efficacy of Ethinylestradiol can be decreased when used in combination with Isotretinoin.
Mestranol The therapeutic efficacy of Mestranol can be decreased when used in combination with Isotretinoin.
Estradiol The therapeutic efficacy of Estradiol can be decreased when used in combination with Isotretinoin.
Estradiol cypionate The therapeutic efficacy of Estradiol cypionate can be decreased when used in combination with Isotretinoin.
Estradiol valerate The therapeutic efficacy of Estradiol valerate can be decreased when used in combination with Isotretinoin.
Estetrol The therapeutic efficacy of Estetrol can be decreased when used in combination with Isotretinoin.
Desogestrel The therapeutic efficacy of Desogestrel can be decreased when used in combination with Isotretinoin.
Levonorgestrel The therapeutic efficacy of Levonorgestrel can be decreased when used in combination with Isotretinoin.
Norethisterone The therapeutic efficacy of Norethisterone can be decreased when used in combination with Isotretinoin.
Ethynodiol diacetate The therapeutic efficacy of Ethynodiol diacetate can be decreased when used in combination with Isotretinoin.
Norgestimate The therapeutic efficacy of Norgestimate can be decreased when used in combination with Isotretinoin.
Drospirenone The therapeutic efficacy of Drospirenone can be decreased when used in combination with Isotretinoin.
Cyproterone acetate The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Isotretinoin.
Gestodene The therapeutic efficacy of Gestodene can be decreased when used in combination with Isotretinoin.
Hydroxyprogesterone caproate The therapeutic efficacy of Hydroxyprogesterone caproate can be decreased when used in combination with Isotretinoin.
Norethynodrel The therapeutic efficacy of Norethynodrel can be decreased when used in combination with Isotretinoin.
Norgestrel The therapeutic efficacy of Norgestrel can be decreased when used in combination with Isotretinoin.
Gestrinone The therapeutic efficacy of Gestrinone can be decreased when used in combination with Isotretinoin.
Lynestrenol The therapeutic efficacy of Lynestrenol can be decreased when used in combination with Isotretinoin.
Chlormadinone The therapeutic efficacy of Chlormadinone can be decreased when used in combination with Isotretinoin.
Norgestrienone The therapeutic efficacy of Norgestrienone can be decreased when used in combination with Isotretinoin.
Quingestanol The therapeutic efficacy of Quingestanol can be decreased when used in combination with Isotretinoin.
Demegestone The therapeutic efficacy of Demegestone can be decreased when used in combination with Isotretinoin.
Nomegestrol acetate The therapeutic efficacy of Nomegestrol acetate can be decreased when used in combination with Isotretinoin.
Megestrol acetate The therapeutic efficacy of Megestrol acetate can be decreased when used in combination with Isotretinoin.
Medroxyprogesterone acetate The therapeutic efficacy of Medroxyprogesterone acetate can be decreased when used in combination with Isotretinoin.
Dienogest The therapeutic efficacy of Dienogest can be decreased when used in combination with Isotretinoin.
Ethanol The risk or severity of adverse effects can be increased when Ethanol is combined with Isotretinoin.
Vitamin A The risk or severity of adverse effects can be increased when Vitamin A is combined with Isotretinoin.
Pitolisant The serum concentration of Isotretinoin can be decreased when it is combined with Pitolisant.
Icosapent Icosapent may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefotiam Cefotiam may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Mesalazine Mesalazine may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefmenoxime Cefmenoxime may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefmetazole Cefmetazole may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Tenofovir disoproxil Tenofovir disoproxil may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Indomethacin Indomethacin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cidofovir Cidofovir may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefpiramide Cefpiramide may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Ceftazidime Ceftazidime may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Loracarbef Loracarbef may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Framycetin Framycetin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefalotin Cefalotin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Nabumetone Nabumetone may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Ketorolac Ketorolac may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Tenoxicam Tenoxicam may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Celecoxib Celecoxib may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefotaxime Cefotaxime may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Tolmetin Tolmetin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Foscarnet Foscarnet may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Rofecoxib Rofecoxib may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Piroxicam Piroxicam may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cephalexin Cephalexin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Fenoprofen Fenoprofen may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Valaciclovir Valaciclovir may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Valdecoxib Valdecoxib may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Diclofenac Diclofenac may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Sulindac Sulindac may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Bacitracin Bacitracin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cephaloglycin Cephaloglycin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Flurbiprofen Flurbiprofen may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Adefovir dipivoxil Adefovir dipivoxil may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Pentamidine Pentamidine may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Etodolac Etodolac may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Mefenamic acid Mefenamic acid may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Acyclovir Acyclovir may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Naproxen Naproxen may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Phenylbutazone Phenylbutazone may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Meloxicam Meloxicam may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Carprofen Carprofen may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefaclor Cefaclor may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Diflunisal Diflunisal may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Ceforanide Ceforanide may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Salicylic acid Salicylic acid may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Meclofenamic acid Meclofenamic acid may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Carboplatin Carboplatin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Oxaprozin Oxaprozin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Ketoprofen Ketoprofen may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Balsalazide Balsalazide may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Ibuprofen Ibuprofen may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefditoren Cefditoren may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Colistimethate Colistimethate may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefuroxime Cefuroxime may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefapirin Cefapirin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefadroxil Cefadroxil may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefprozil Cefprozil may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Ceftriaxone Ceftriaxone may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Olsalazine Olsalazine may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Lumiracoxib Lumiracoxib may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefamandole Cefamandole may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefazolin Cefazolin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefonicid Cefonicid may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefoperazone Cefoperazone may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefotetan Cefotetan may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Cefoxitin Cefoxitin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
Ceftizoxime Ceftizoxime may decrease the excretion rate of Isotretinoin which could result in a higher serum level.

Target Protein

Retinoic acid receptor gamma RARG
Retinoic acid receptor alpha RARA

Referensi & Sumber

Synthesis reference: Ashok Kumar, Dharmendra Singh, Ganesh Devidas Mahale, Ragnesh Kumar Rana, Mahesh Kharade, "PROCESS FOR PREPARATION OF HIGHLY PURE ISOTRETINOIN." U.S. Patent US20080207946, issued August 28, 2008.
Artikel (PubMed)
  • PMID: 6957421
    Khoo KC, Reik D, Colburn WA: Pharmacokinetics of isotretinoin following a single oral dose. J Clin Pharmacol. 1982 Aug-Sep;22(8-9):395-402.
  • PMID: -
    Miastkowska M, Sikora E, Ogonowski J, Zielina M, Łudzik A: The kinetic study of isotretinoin release from nanoemulsion Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2016 Dec 5;510:63-68.
  • PMID: 6120808
    Vane FM, Bugge CJ: Identification of 4-oxo-13-cis-retinoic acid as the major metabolite of 13-cis-retinoic acid in human blood. Drug Metab Dispos. 1981 Nov-Dec;9(6):515-20.
  • PMID: 20436884
    Layton A: The use of isotretinoin in acne. Dermatoendocrinol. 2009 May;1(3):162-9. doi: 10.4161/derm.1.3.9364.
  • PMID: 1352212
    Chien DS, Sandri RB, Tang-Liu DS: Systemic pharmacokinetics of acitretin, etretinate, isotretinoin, and acetylenic retinoids in guinea pigs and obese rats. Drug Metab Dispos. 1992 Mar-Apr;20(2):211-7.
  • PMID: 17224928
    Veal GJ, Cole M, Errington J, Pearson AD, Foot AB, Whyman G, Boddy AV: Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma - a study of the United Kingdom Children's Cancer Study Group. Br J Cancer. 2007 Feb 12;96(3):424-31. doi: 10.1038/sj.bjc.6603554. Epub 2007 Jan 16.
  • PMID: 8548998
    Aubin S, Lorette G, Muller C, Vaillant L: Massive isotretinoin intoxication. Clin Exp Dermatol. 1995 Jul;20(4):348-50.
  • PMID: 6461675
    Brazzell RK, Colburn WA: Pharmacokinetics of the retinoids isotretinoin and etretinate. A comparative review. J Am Acad Dermatol. 1982 Apr;6(4 Pt 2 Suppl):643-51.
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