Accutane (Isotretinoin) Metabolism and Energy Expenditure: What the Evidence Shows

How food changes absorption

In a crossover study, 74 healthy adults received a single 80 mg oral dose fasted and after a standardized high-fat meal. AUC was 10,004 versus 3,703 ng h/mL, Cmax was 862 versus 301 ng/mL, and Tmax was 5.3 versus 3.2 hours [1]. The half-life was 21 hours in both conditions [1].

The Accutane label says to take isotretinoin with a meal and states that failure to take it with food significantly decreases absorption [1]. The Absorica and Absorica LD label allows dosing without regard to meals and states that the two products are not substitutable mg for mg [4].

How isotretinoin is metabolized

At least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin) and 4-oxo-retinoic acid (4-oxo-tretinoin) [1]. Retinoic acid and 13-cis-retinoic acid are geometric isomers with reversible interconversion; isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin [1]. At steady state, exposure to 4-oxo-isotretinoin was about 3.4 times that of isotretinoin [1].

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are CYP2C8, CYP2C9, CYP3A4 and CYP2B6 [1]. Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin [1]. After an 80 mg dose, metabolites and conjugates were ultimately excreted in feces and urine in relatively equal amounts, with a combined total of 65% to 83% [1].

Half-life and clearance

The 74-adult study reported a mean half-life of about 21 hours, unchanged by food [1]. In 38 pediatric patients 12 to 15 years old, the mean half-life was 15.7 hours for isotretinoin and 23.1 hours for 4-oxo-isotretinoin [1]. A 1982 review gives apparent half-lives of 10 to 20 hours for isotretinoin and 24 to 29 hours for 4-oxo-isotretinoin [5].

Lipids and triglycerides

The Accutane label reports marked serum triglyceride elevations in approximately 25% of patients in clinical trials, a decrease in high-density lipoprotein cholesterol in approximately 15%, and an increase in cholesterol in about 7% [1]. These effects were reversible upon cessation, and the label says lipid determinations should be performed before treatment and at intervals until the response is established, usually within 4 weeks [1]. The Absorica label also lists pancreatitis and says treatment should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level [4].

A retrospective cohort of 13,772 patients found cumulative incidence rates of new abnormalities of 44% for triglycerides, 31% for total cholesterol and 11% for transaminase during isotretinoin treatment [6].

A 20-week study of 60 patients found mean triglyceride levels rose by 46.3 mg/dL in men (P<0.0001) and 52.3 mg/dL in women (P<0.002). Nine of 53 patients (17%) who completed 20 weeks acquired hypertriglyceridemia of 200 to 600 mg/dL. Mean lipoprotein lipase and hepatic triglyceride lipase levels did not change significantly, and lipids returned to baseline by 8 weeks after discontinuation [7].

Thermogenesis and brown fat

In cultured brown adipocytes, retinoic acid increased UCP mRNA severalfold. The induction was independent of adrenergic pathways or protein synthesis, and retinoic acid receptor alpha was more effective than retinoid X receptor, with a mixture of the two most effective [2].

In adult mice, an acute injection of all-trans retinoic acid reduced body fat, raised rectal temperature, and up-regulated UCP1 and UCP2 mRNA in white adipose tissue, along with PGC-1alpha and other genes. Adipocyte size fell, and multilocular adipocytes increased [3].

These experiments used retinoic acid, not oral isotretinoin, and the measured outcomes were UCP expression and rectal temperature in animals or cells [2][3].

Thyroid hormones and weight

One study measured hormones in 47 acne patients before and after 3 months of isotretinoin. Free T3, TSH and TSH receptor antibody levels fell significantly (p<0.001, p<0.02 and p<0.02), as did luteinizing hormone, prolactin, total testosterone, morning cortisol and adrenocorticotropic hormone [8]. The authors described this as mild suppression of pituitary hormone levels [8].

The Absorica label lists weight loss, weight fluctuation and decreased appetite as adverse reactions and states that some frequencies cannot be reliably estimated [4]. It also lists alterations in blood sugar [4].

Drug interactions that affect metabolism

The label says to avoid supplements containing vitamin A because isotretinoin is closely related to vitamin A [4][1]. It also says to avoid concomitant use of tetracyclines because isotretinoin has been associated with intracranial hypertension, and some cases involved tetracyclines [4][1].

In a study of 31 premenopausal women with severe recalcitrant nodular acne, isotretinoin at 1 mg/kg/day did not cause clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone [1]. The Absorica label says it is not known whether there is an interaction with other oral contraceptives [4].