Isotretinoin, or 13-cis-retinoic acid can undergo reversible cis-trans isomerization to all-trans-retinoic acid. Isotretinoin undergoes 4-hydroxylation to 4-hydroxy-13-cis-retinoic acid, which is oxidized to the main metabolite 4-oxo-13-cis-retinoic acid.. All-trans-retinoic acid undergoes 4-hydroxylation to 4-hydroxy-all-trans-retinoic acid, which is oxidized to 4-oxo-all-trans-retinoic acid. 4-oxo-13-cis-retinoic acid can undergo reversible cis-trans isomerization to 4-oxo-all-trans-retinoic acid.
... In human volunteers and patients, one major blood metabolite of isotretinoin is 4-oxo-isotretinoin which undergoes slower elimination than isotretinoin and may itself be a participant in teratogenesis.
This paper reviews the teratogenicity of isotretinoin in regard to aspects of species variation, toxicokinetics, and metabolism. The insensitive species (rat, mouse) eliminate the drug rapidly through detoxification to the beta-glucuronide; also, placental transfer is limited in these species. On the other hand, in sensitive species (primates), the drug is predominantly metabolized to the active 13-cis-4-oxo-retinoic acid; placental transfer is more extensive here. The beta-glucuronides showed limited placental transfer in all species examined; these metabolites exhibited very low, if any, measurable concentrations in the human. The 13-cis-retinoic acid is not appreciably bound to cellular retinoid-binding proteins or nuclear receptors and exhibits low tissue distribution and placental transfer. Its access to the nucleus may be extensive. Because of the long half life of 13-cis-retinoic acid, continuous isomerization results in significant area under the concentration-time curve levels of all-trans-retinoic acid in the mouse, monkey and the human; the all-trans-retinoic acid formed is extensively distributed across the placenta and may be an important factor that contributes to the teratogenic potency of 13-cis-retinoic acid. Isomerization cannot explain the teratogenic effects of 13-cis-retinoic acid in the rat and rabbit. It is concluded that the high teratogenic activity of isotretinoin in sensitive species (human, monkey) is related to slow elimination of the 13-cis-isomer, to metabolism to the 4-oxo-derivative, to increased placental transfer, to continuous isomerization and significant exposure of the target tissue to all-trans-retinoic acid; and to lack of binding to cytoplasmic retinoid binding proteins that could possibly result in ready access to the nucleus.
Isotretinoin is metabolized in the liver by the cytochrome P-450 (CYP) microsomal enzyme system, principally by CYP2C8, CYP2C9, CYP3A4, and CYP2B6 isoenzymes, to several metabolites (e.g., 4-oxo-isotretinoin, retinoic acid [tretinoin], and 4-oxo-retinoic acid [4-oxo-tretinoin]). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion, and the administration of one isomer will give rise to the other. Isotretinoin also is irreversibly oxidized to 4-oxo-isotretinoin, which forms its own geometric isomer, 4-oxo-tretinon. All of these metabolites possess retinoid activity that is more than that of the parent compound in some in vitro models. However, the clinical importance of these models is unknown. Concurrent administration of food has been shown to increase the extent of formation of all metabolites in plasma when compared to administration of isotretinoin under fasted conditions. In addition, the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.
IDENTIFICATION AND USE: 13-cis-Retinoic acid (Isotretinoin) is a dermatological agent. HUMAN STUDIES: Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Acute pancreatitis, including rare cases of fatal hemorrhagic pancreatitis, has been reported in patients with elevated or normal serum triglyceride concentrations receiving isotretinoin. Skeletal abnormalities, similar to those occurring with high dosages of systemically administered vitamin A, have occurred in patients receiving isotretinoin therapy. Some evidence suggests that long-term, high-dosage, or multiple courses of isotretinoin therapy may have more of an effect on the musculoskeletal system than a single course of therapy. Between October 1982 and June 1985 the Adverse Drug Reaction Reporting System received reports of 104 suspected adverse reactions occurring in 93 patients who took isotretinoin. Adverse reactions involving the skin and mucous membranes, central nervous system, musculoskeletal system, pregnancy, and eyes were most commonly reported. Severe headache was the most frequently reported adverse reaction. Isotretinoin ranks in the top 10 of the US Food and Drug Administration's database of drugs associated with reports of depression and suicide attempts. However, this association is still controversial because up to 5.6% of patients with moderate acne may have pre-existing suicidal ideations, improvement of acne often reduces associated depression, and isotretinoin users are reportedly no more likely than those taking antibiotics for acne to have depression or commit suicide. Despite extensive precautions for its use, isotretinoin remains a cause of major birth defects, including sensorineural, conductive or mixed hearing loss. There is a report of a newborn with asymmetric crying face and other anomalies whose mother had taken isotretinoin during the first month of pregnancy. Two infants with prominent frontal bossing, hydrocephalus, microphthalmia, and small, malformed, low-set, undifferentiated ears were born to mothers who had taken isotretinoin in the first trimester of pregnancy. A Dandy-Walker malformation, microcephaly, hypertelorism, small ear canals, cleft palate, small mouth, and congenital heart disease were also observed. Isotretinoin is a potent teratogen in man. Maternal ingestion early in pregnancy leads to a distinct clinical pattern of anomalies. In human volunteers and patients, one major blood metabolite of isotretinoin is 4-oxo-isotretinoin which undergoes slower elimination than isotretinoin and may itself be a participant in teratogenesis. ANIMAL STUDIES: In male and female rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day. In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day. A clinical dose (1 mg/kg/day) of the drug in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. ECOTOXICITY STUDIES: Japanese flounder, Paralichthys olivaceus, at 6-9 days post-hatching, all retinoic acid isomers induced deformities in the lower jaw, caudal fin and vertebrae. In the lower jaw, growth retardation of the dentary was evident. In the vertebrae, the major abnormalities were hypertrophy of the centrum, central fusion, and an increase in the number of abdominal vertebrae. Caudal fin deformities included deformity of caudal bone complex and absence of the entire caudal fin. The absence of the hypural primordium was the first sign of abnormality in caudal fin development, and resulted in complete blocking of the caudal fin development.
Liver test abnormalities occur in up to 15% of patients on isotretinoin, although marked elevations above three times the upper limit of normal or requiring drug discontinuation are rare (
Patients reach a maximum concentration of 74-511ng/mL after 1-4 hours following a 100mg oral dose. Isotretinoin is better absorbed with a high fat meal and bioavailability may change from one brand to another. 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. 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.
Isotretinoin and its metabolites are conjugated and excreted in the urine and feces in similar amounts. 53-74% of an oral dose is eliminated as unchanged isotretinoin in the feces.
The volume of distribution in humans is unknown because there is no intravenous preparation. In a study of pediatric patients with neuroblastoma the volume of distribution was found to be 85L. The volume of distribution was also found to be 2432mL/kg in guinea pigs and 1716mL/kg in obese rats.
The clearance of isotretinoin is 15.9L/h in pediatric patients with neuroblastoma. Clearance is also 21.3mL/min/kg in guinea pigs and 7.2mL/min/kg in obese rats.
Following oral administration of isotretinoin, there is an apparent lag time of about 0.5-2 hours before the drug appears in systemic circulation. The lag time is thought to result from disintegration of the capsule and subsequent dissolution of the drug in GI contents. Absorption of the drug after this lag time is rapid. The actual bioavailability of orally administered isotretinoin has not been determined in humans, but studies in animals indicate that about 25% of an oral dose of the drug reaches systemic circulation as unchanged isotretinoin The low bioavailability observed in animals may result from biodegradation of the drug in the GI lumen and/or metabolism of the drug during absorption (in the GI mucosa) and first pass through the liver. Food and/or milk increase GI absorption of isotretinoin. Peak blood isotretinoin concentrations are slightly delayed and substantially increased and the area under the blood concentration-time curve (AUC) of the drug is approximately 1.5-2 times greater when isotretinoin is administered 1 hour before, concomitantly with, or 1 hour after a meal than when the drug is administered in the fasting state. Because of its high lipophilicity, oral absorption of isotretinoin is enhanced when the drug is administered with a high-fat meal. In a crossover study of 74 healthy adults who received a single 80-mg isotretinoin dose (as two 40-mg capsules) under fasted and fed conditions, both the peak plasma concentration and total area under the plasma concentration-time curve (AUC) of the drug were more than doubled when isotretinoin was administered immediately after a standardized high-fat meal compared with administration in the fasted state. Because the observed elimination half-life of the drug remained unchanged, it is suggested that food appears to increase the bioavailability of isotretinoin without altering its disposition. The time to peak concentration was also increased with food and may be related to a longer absorption phase. Consequently, the manufacturers recommend that isotretinoin capsules always be administered with food.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
申请人：Xu Feng
公开号：US20100120727A1
公开（公告）日：2010-05-13
In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.
[EN] FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLE CONDENSÉS UTILISÉS EN TANT QU'INHIBITEURS DE JAK
申请人：ALMIRALL SA
公开号：WO2017220431A1
公开（公告）日：2017-12-28
Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
[EN] COMPOUNDS THAT MODULATE EGFR ACTIVITY AND METHODS FOR TREATING OR PREVENTING CONDITIONS THEREWITH<br/>[FR] COMPOSÉS MODULANT L'ACTIVITÉ DES RÉCEPTEURS EGFR ET MÉTHODES POUR TRAITER OU PRÉVENIR DES TROUBLES À L'AIDE DE CEUX-CI
申请人：GATEKEEPER PHARMACEUTICALS INC
公开号：WO2011140338A1
公开（公告）日：2011-11-10
Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.
提供了用于治疗或预防激酶介导的疾病的化合物和方法。
[EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
申请人：HOFFMANN LA ROCHE
公开号：WO2021234004A1
公开（公告）日：2021-11-25
The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.
