Clinical pharmacokinetics of tretinoin

Mario B. Regazzi, Isabella Iacona, Cristina Gervasutti, Mario Lazzarino, Salvatore Toma

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Recent reports of the dramatic antitumour effect of tretinoin (all-trans retinoic acid) in patients with acute promyelocytic leukaemia (APL) have generated a great deal of interest in the use of this drug as a chemopreventive and therapeutic agent. However, the biological efficacy of tretinoin is greatly impaired by (presumably) an induced hypercatabolism of the drug leading to reduced tretinoin sensitivity and resistance. Several pharmacokinetic studies have shown that plasma drug exposure [as measured by the plasma area under the concentration-time curve (AUC∞)] declines substantially and rapidly when the drug is administered in a long term daily tretinoin regimen. These observations led to the hypothesis that the rapid development of acquired clinical resistance to tretinoin may have a pharmacological basis and result from an inability to present an effective drug concentration to the leukaemic cells during continuous treatment. The principal mechanisms proposed to explain the increased disappearance of tretinoin from plasma include: (i) decreased intestinal absorption; (ii) enhanced enzymatic catabolism; and (iii) the induction of cytoplasmic retinoic acid binding proteins (CRABP), which leads to increased drug sequestration. The most favoured explanation is that continuous tretinoin treatment acts to induce drug catabolism by cytochrome P450 (CYP) enzymes. Several strategies aimed at preventing or overcoming induced tretinoin resistance have been, and are being, planned. These strategies include intermittent dose administration, administration of pharmacological inhibitors of CYP oxidative enzymes, combination with interferon-α and intravenous administration of liposome-encapsulated tretinoin. As these strategies are now under investigation and the number of patients enrolled is small, further studies are needed to determine the efficacy and toxicity of these new schedules of drug administration. In this article we provide an overview of the relevant aspects of tretinoin physiology and pharmacokinetics, and summarise the current status of knowledge to help in the better optimisation of tretinoin administration.

Original languageEnglish
Pages (from-to)382-402
Number of pages21
JournalClinical Pharmacokinetics
Volume32
Issue number5
Publication statusPublished - 1997

Fingerprint

Tretinoin
Pharmacokinetics
Cytochrome P-450 Enzyme System
Pharmaceutical Preparations
Drug Administration Schedule
Pharmacology
Acute Promyelocytic Leukemia
Retinoic Acid Receptors
Intestinal Absorption
Liposomes
Intravenous Administration
Interferons
Therapeutics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Regazzi, M. B., Iacona, I., Gervasutti, C., Lazzarino, M., & Toma, S. (1997). Clinical pharmacokinetics of tretinoin. Clinical Pharmacokinetics, 32(5), 382-402.

Clinical pharmacokinetics of tretinoin. / Regazzi, Mario B.; Iacona, Isabella; Gervasutti, Cristina; Lazzarino, Mario; Toma, Salvatore.

In: Clinical Pharmacokinetics, Vol. 32, No. 5, 1997, p. 382-402.

Research output: Contribution to journalArticle

Regazzi, MB, Iacona, I, Gervasutti, C, Lazzarino, M & Toma, S 1997, 'Clinical pharmacokinetics of tretinoin', Clinical Pharmacokinetics, vol. 32, no. 5, pp. 382-402.
Regazzi MB, Iacona I, Gervasutti C, Lazzarino M, Toma S. Clinical pharmacokinetics of tretinoin. Clinical Pharmacokinetics. 1997;32(5):382-402.
Regazzi, Mario B. ; Iacona, Isabella ; Gervasutti, Cristina ; Lazzarino, Mario ; Toma, Salvatore. / Clinical pharmacokinetics of tretinoin. In: Clinical Pharmacokinetics. 1997 ; Vol. 32, No. 5. pp. 382-402.
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