Pharmacokinetics

Tretinoin

Systemic tretinoin is greater than 95% bound to plasma proteins, primarily albumin. The distribution of tretinoin has not been determined. Tretinoin is metabolized by the cytochrome P450 hepatic enzyme system. The metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. Tretinoin appears to induce its own metabolism. An approximately 10-fold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide is observed after 2—6 weeks of continuous dosing when compared with baseline.

Topical Route: Following topical application, a minimal amount of drug is absorbed systemically. There is no expected difference in the systemic absorption of tretinoin from the microsphere formulation. Prolonged treatment or application to large body surface areas can enhance systemic absorption.

Niacinamide

Nicotinic acid may be administered by the oral or parenteral routes. Nicotinamide is administered orally. Niacin is widely distributed throughout the body and it concentrates in the liver, spleen, and adipose tissue. Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. Niacin is conjugated with glycine to form nicotinuric acid (NUA), which is then excreted in the urine. Some reversible metabolism from NUA back to niacin may occur in small amounts. The other pathway results in the formation of NAD. Nicotinamide is most likely released after the formation of NAD. Nicotinamide does not have hypolipidemic activity, and is further metabolized in the liver to produce N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is metabolized to two other N-methylated compounds known as 2PY and 4PY, which are excreted in the urine. The formation of 2PY predominates over 4PY in humans. Roughly 12% of nicotinic acid is excreted unchanged in the urine with normal dosages. Greater proportions of niacin are renally excreted unchanged as dosages exceed 1000 mg/day and metabolic pathways become saturated.

Vitamin E Acetate

Vitamin E is usually administered orally but may be given parenterally as part of a multivitamin injection in parenteral nutrition. Topical products are also available. Absorption of vitamin E from the GI tract is dependent upon biliary and pancreatic secretions, micelle formation and uptake into enterocytes and chylomicron secretion.(7) Systemically absorbed Vitamin E is bound to plasma beta-lipoproteins and is widely distributed, particularly in fat tissues. Vitamin E also crosses the placenta and is distributed to breast milk. Total body stores in adults are estimated to be 3 to 8 grams, which appear adequate for greater than 4 years of a vitamin E-deficient diet. The plasma half-life of alpha-tocopherol is 48 to 60 hours, while the synthetic form has a half-life of 15 hours. Alpha-tocopherol undergoes recirculation from the liver to the plasma and this recirculation plays a role in its long half-life. The liver-plasma recirculation is dependent upon alpha-tocopherol transfer protein (alpha-TTP) and results in almost the daily replacement of nearly the entire circulating alpha-tocopherol pool.(34) The different forms of vitamin E have differing affinities for alpha-TTP, which leads to the differing serum concentrations. Due to its low absorption from the intestine, the major route of elimination of vitamin E is fecal elimination. Excess alpha-tocopherol and other forms of vitamin E are probably excreted unchanged in the bile. Small amounts of other vitamin E metabolites are eliminated in the urine.(7)

Following topical application of vitamin E, vitamin E is substantially absorbed in the skin, with no evidence of conversion within the skin to free alpha-tocopherol. In one study, there was no evidence of systemic availability or biotransformation of topically applied alpha-tocopherol acetate.(35)