Variability in the oral bioavailability of all-trans-retinoic acid.
BACKGROUND
Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies.


OBJECTIVE
This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy.


METHODS
Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography.


RESULTS
Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase.


CONCLUSIONS
The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.
Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
P C
PC
Adamson
H C
HC
Pitot
F M
FM
Balis
J
J
Rubin
R F
RF
Murphy
D G
DG
Poplack
D000230:Adenocarcinoma / Q000188:drug therapy; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001682:Biological Availability; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy; D005260:Female; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D014212:Tretinoin