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Planta Med 2020; 86(04): 276-283
DOI: 10.1055/a-1087-8374
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Pharmacokinetics, Pharmacodynamics and Dermal Distribution of 5-Methoxypsoralen Based on a Physiologically Based Pharmacokinetic Model to Support Phytotherapy Using Brosimum gaudichaudii

Frederico Severino Martins
1   Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil
,
Sherwin K.B. Sy
2   Department of Statistics, State University of Maringá, Maringá, Brazil
,
Maria José Vieira Fonseca
1   Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil
,
Osvaldo de Freitas
1   Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, São Paulo, Brazil
› Author AffiliationsSupported by: Capes and São Paulo Research Foundation – FAPESP grant number 12/15979-0
Further Information

Publication History

received 16 October 2019
revised 28 November 2019

accepted 31 December 2019

Publication Date:
22 January 2020 (online)

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Abstract

The treatment of vitiligo includes the combination of psoralens and ultraviolet type A exposure. Psoralens belong to a group of natural furanocoumarins that cause the skin to become sensitive temporarily to ultraviolet type A. The aim of this study was to develop a physiologically based pharmacokinetic model of 5-MOP from Brosimum gaudichaudii to support psoralen and ultraviolet type A therapy. A study of rats was used to establish and validate rat tissue distribution. The same chemical-specific parameters used in the rat model were also employed in the human model to project human pharmacokinetics. The highest exposures in the rats were in the brain and skin. Following a single dose of 1.2 mg/kg 5-MOP in humans, the model predicted a maximum concentration of 20 ng/mL and an area under the curve of 125 ng.h/mL, matching clinical results. The half-maximum melanogenesis concentrations in B16F10 cells were 29.5, 18.5, 11.5, and 6.5 ng/mL for synthetic 5-MOP, synthetic 5-MOP with ultraviolet type A, B. gaudichaudii alone, and B. gaudichaudii plus ultraviolet type A, respectively. Physiologically based pharmacokinetic model prediction in humans supported a once-every-two-day regimen for optimal melanin production. This type of framework can be applied to support strategies for dose selection and to investigate the impact of drugs on melanocyte recovery.

Key words

vitiligo - skin - psoralen - PUVA - Brosimum gaudichaudii - Moraceae
 

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