Variability in the oral bioavailability of all-trans-retinoic acid

P. C. Adamson, Henry Clement Pitot, F. M. Balis, J. Rubin, R. F. Murphy, D. G. Poplack

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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. Purpose: 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 μM 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)993-996
Number of pages4
JournalJournal of the National Cancer Institute
Volume85
Issue number12
StatePublished - 1993

Fingerprint

Tretinoin
Biological Availability
Dose
Acids
Plasma
Plasmas
Absorption
Drugs
Acute Promyelocytic Leukemia
Pharmacokinetics
Leukemia
Doubling
Acute
Fold
Drug Monitoring
High-performance Liquid Chromatography
High performance liquid chromatography
Gelatin
Pharmaceutical Preparations
Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

Cite this

Adamson, P. C., Pitot, H. C., Balis, F. M., Rubin, J., Murphy, R. F., & Poplack, D. G. (1993). Variability in the oral bioavailability of all-trans-retinoic acid. Journal of the National Cancer Institute, 85(12), 993-996.

Variability in the oral bioavailability of all-trans-retinoic acid. / Adamson, P. C.; Pitot, Henry Clement; Balis, F. M.; Rubin, J.; Murphy, R. F.; Poplack, D. G.

In: Journal of the National Cancer Institute, Vol. 85, No. 12, 1993, p. 993-996.

Research output: Contribution to journalArticle

Adamson, PC, Pitot, HC, Balis, FM, Rubin, J, Murphy, RF & Poplack, DG 1993, 'Variability in the oral bioavailability of all-trans-retinoic acid', Journal of the National Cancer Institute, vol. 85, no. 12, pp. 993-996.
Adamson PC, Pitot HC, Balis FM, Rubin J, Murphy RF, Poplack DG. Variability in the oral bioavailability of all-trans-retinoic acid. Journal of the National Cancer Institute. 1993;85(12):993-996.
Adamson, P. C. ; Pitot, Henry Clement ; Balis, F. M. ; Rubin, J. ; Murphy, R. F. ; Poplack, D. G. / Variability in the oral bioavailability of all-trans-retinoic acid. In: Journal of the National Cancer Institute. 1993 ; Vol. 85, No. 12. pp. 993-996.
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abstract = "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. Purpose: 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 μM 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. Conclusion: 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.",
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