A physiologically based pharmacokinetic model for retinoic acid and its metabolites

doi:10.1016/S0190-9622(97)70063-X

Journal of the American Academy of Dermatology

Volume 36, Issue 3, Supplement, March 1997, Pages S77-S85

https://doi.org/10.1016/S0190-9622(97)70063-X Get rights and content

Abstract

Background: A physiologically based pharmacokinetic (PBPK) model for all- trans -retinoic acid (tretinoin) was developed to provide a coherent description of tretinoin absorption, distribution, metabolism, and excretion across species and routes of administration. Objective: The goal of developing such a model is to provide a measure of internal dose that would be a biologically relevant surrogate for administered dose in assessing human teratogenic risk from topically applied tretinoin emollient cream. Methods: The developed PBPK model included compartments for plasma, liver, gut, intestinal lumen, fat, skin, richly and slowly perfused tissues, placenta, and embryo. Tretinoin metabolism to 13- cis retinoic acid, oxidation, and glucuronidation were incorporated. Dose surrogates, including the maximum plasma concentration (C _max ) and area under the concentration-versus-time curve were calculated from the model. Results: The ability of the model to predict tretinoin pharmacokinetics and to extrapolate across species and routes of administration was tested and validated. Model-derived estimates of dose surrogates demonstrated that the internal exposure to retinoids after topical treatment with 0.05% tretinoin emollient cream is minimal in comparison to that for teratogenic oral doses. The ratio of areas under the curve for total active retinoids after teratogenic oral doses in monkeys versus therapeutic topical doses in human beings, for example, was greater than 450,000 to 1. Conclusion: For topical application of tretinoin in human beings, detoxification via the glucuronidation pathway predominates, resulting in a much lower internal exposure to active retinoids than was inferred from total radioactivity data. The model predicts that topical application of tretinoin results in an internal exposure that is four to six orders of magnitude lower than a minimally teratogenic dose. (J Am Acad Dermatol 1997;36:S77-S85.)

Section snippets

MODEL DESCRIPTION

The PBPK model developed for tretinoin (Fig. 1) provides a full physiologic description for this chemical with compartments for plasma, liver, gut, intestinal lumen, fat, skin, richly perfused tissues, slowly perfused tissues, placenta, and embryo.

. PBPK model for all- trans -retinoic acid (tretinoin).

The symbols used in the conceptual model are defined in Table I . Both oxidation (to the 4-oxo derivative) and glucuronidation of tretinoin are described with saturable kinetics. Conversion to the

OBTAINING VALUES FOR MODEL FACTORS

The physiologic values for adult animals were obtained from the literature 4, 5, 6, 7 and from an ongoing effort sponsored by the International Life Science Institute to establish standard values for each species (Stan Linstedt, PhD, personal communication, 1992). Gestational values were based on previous modeling of rats. 8, 9 Partition coefficients were determined from distribution studies with mice ¹⁰ and human placenta. ¹¹ The tretinoin volume of distribution calculated with these

MODEL SIMULATION AND VALIDATION

Model-simulated plasma concentration curves for tretinoin after oral doses in rats and monkeys show close agreement with previously reported data. Fig. 2 shows the ability of the model to describe the kinetics of tretinoin in rats for three intravenous doses.¹³

. Observed (points) and model-predicted (curves) mean plasma tretinoin concentrations (nanograms per milliliter) after intravenous administration of tretinoin to rats. (Plus) , 0.015 mg/kg; ( triangle) , 0.25 mg/kg; and (circle) 5.0 mg/kg.

RESULTS AND DISCUSSION

The PBPK model for 0.05% tretinoin emollient cream was used to predict plasma concentrations of parent drug and metabolites after topical exposure. An example of a predicted time course for plasma concentrations after topical exposure to 100 mg of radiolabeled 0.05% tretinoin emollient cream is shown in Fig. 7 .

. Predicted time course of plasma concentrations after topical exposure to 100mgtritiated tretinoin in human beings. Solid line , Total plasma radioactivity; dashed line ,tretinoin.

The

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Journal of the American Academy of Dermatology

Abstract

Section snippets

MODEL DESCRIPTION

OBTAINING VALUES FOR MODEL FACTORS

MODEL SIMULATION AND VALIDATION

RESULTS AND DISCUSSION

References (21)

Methotrexate pharmacokinetics

J Pharm Sci

Distribution and excretion of 2,2`,4,4`,5,5`hexabromobiphenyl in rats and man: pharmacokinetic model predictions

Toxicol Appl Pharmacol

Physiologically based pharmacokinetic modeling of the pregnant rat: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid

Toxicol Appl Pharmacol

A physiologically based kinetic model of rat and mouse gestation: disposition of a weak acid

Toxicol Appl Pharmacol

Metabolites of all- trans -retinoic acid in bile: identification of all- trans - and 13- cis -retinoyl glucuronides

J Biol Chem

Dose-dependent kinetics of all- trans -retinoic acid in rats: plasma levels and excretion into bile, urine, and faeces

Biochem Pharmacol

The percutaneous absorption of topically applied tretinoin and its effect on endogenous concen-trations of tretinoin and its metabolites following single doses or long-term use

J Am Acad Dermatol

Preclinical and clinical toxicology of selected retinoids

A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats

J Am Acad Dermatol

Toxicokinetics: an analytical tool for assessing chemical hazards to man

Aviat Space Environ Med

Cited by (63)

Disease progress models

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Commentary on the safety of topical vitamin A in cosmetics

Evaluation of simple in vitro to in vivo extrapolation approaches for environmental compounds

A physiologically based pharmacokinetic model for retinoic acid and its metabolites☆,☆☆

Abstract

Section snippets

MODEL DESCRIPTION

OBTAINING VALUES FOR MODEL FACTORS

MODEL SIMULATION AND VALIDATION

RESULTS AND DISCUSSION

J Pharm Sci

Toxicol Appl Pharmacol

Toxicol Appl Pharmacol

Toxicol Appl Pharmacol

J Biol Chem

Biochem Pharmacol

J Am Acad Dermatol

J Am Acad Dermatol

Toxicokinetics: an analytical tool for assessing chemical hazards to man

Aviat Space Environ Med