Isotretinoin is a drug that is found in the retinoid family. This means that is expresses Vitamin A activity when metabolized in the body. Isotretinoin is listed as a pregnancy risk factor "X"  by the Food and Drug Administration because it causes severe birth defects and mental retardation when taken during pregnancy or shortly before.

 

 

Absorption of isotretinoin takes anywhere between thirty minutes to two hours, but the rate is increased when taken concomitantly with a high-fat meal. Once absorbed, the drug is metabolized by CYP's primarily in the liver. In humans, the primary pathway of metabolism is isomerization, conversion to an enantiomer. The main metabolite 13-cis-4-oxo-retinoic acid; this is thought to be the compound that causes the teratogenic effects of this drug. The secondary pathway is glucuronidation where the metabolite is conjugated with glucuronide yielding Β-glucuronide which is found less frequently than the 4-oxo metabolite. Glucuronidation is responsible for detoxifying the drug making the compound easier to be excreted, while isomerization yields a compound that takes longer to break down and excrete.

Research

Epidemiological studies have been conducted world wide questioning women on their consumption of isotretinoin before and during pregnancy. Results have shown that due to the lack of information and compliance, teratogenicity is still a problem. Many countries do not have programs in place to educate or monitor drug consumption.

Studies on the cynamologous monkey have shown that the primate is an accurate model for human metabolism as it produces 13-cis-4-oxo-retinoic acid as the primary metabolite. Similar teratogenic effects such as low IQ and skull malformations were also noted in the monkey's offspring. The rodent model shows Β-glucuronide as the primary metabolite. The studies with this model have shown that exposure during gestation greatly effects cerebral function and cerebellar coordination. Other studies of tissues have implied that isotretinoin causes incomplete closure of the notochord and also affects neural crest cell migration in the embryo. The Hox genes are also thought to be affected, but the mechanism is not yet known.

Teratogenic Effects

Isotretinoin causes anotia, hydrocephaly, microcephaly, mental retardation, and skull malformations such as cleft palate and eyes that are close together. Adverse effects depend on species, dose, and stage of pregnancy. Studies show that doses as low as 0.4 mg/kg/day could cause teratogenicity in humans.

Awareness

Pregnancy Prevention Programs (PPP) – Established in 1989 by the FDA aimed at informing patients of the risks of isotretinoin.

System to Manage Accutane Related Teratogenicity (SMART) - The 2004 amendment to the PPP that required the patient to submit a pregnancy test before the beginning of therapy and the use of warning labels on packages that contain isotretinoin.

iPLEDGE – A program that became mandatory in 2006 in the United States require prescribers and pharmacists dispensing isotretinoin to register with the program. Patients of childbearing age must be able to submit two negative pregnancy tests prior to therapy and a negative test each month for the duration of therapy. The patient must also submit a comprehension test to verify that they understand the regulations and the risks involved with isotretinoin therapy.