Food-induced increase in bioavailability of 5-methoxypsoralen

Ehrsson, Hans; Wallin, Inger; Ros, Anne‐Marie; Eksborg, Staffan; Berg, Mats

doi:10.1007/bf00194409

Cited by 11 publications

(6 citation statements)

References 20 publications

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“…The reason for this discrepancy could be due to the interaction between 5-MOP and other compounds in the extract matrix, the involvement of CYP enzymes or transporters [18], or due to drug precipitation in the GI tract. Numerous studies already reported large differences in oral absorption of 5-MOP due to the influence of formulation, particle size, and food effects in humans [19][20][21]. Our study was carried out in specific experimental conditions that avoided saturation and precipitation of the drug in the GI tract.…”

Section: Pharmacokineticmentioning

confidence: 99%

“…The same chemical-specific parameters, V ss /F, and intestinal permeability [27] information that were used in the rat model were also employed in the human PBPK model. After the model was extrapolated to humans, the predicted plasma concentrations in humans were validated by data from an experimental human pharmacokinetic study using a single oral dose of 1.2 mg/kg 5-MOP [21]. The exposure parameters determined from the PBPK model for 5-MOP were C max , t max , and AUC 0-16 h .…”

Section: Predictions Of Human Pharmacokinetics Using a Physiologicallmentioning

confidence: 99%

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

Martins¹,

Fonseca³

et al. 2020

Planta Med

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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.

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Section: Pharmacokineticmentioning

confidence: 99%

Section: Predictions Of Human Pharmacokinetics Using a Physiologicallmentioning

confidence: 99%

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

Martins¹,

Fonseca³

et al. 2020

Planta Med

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“…14,16 This enhanced dissolution rate in the presence of food may be the reason for the improved bioavailability observed after oral administration of several lipophilic drugs such as danazol, 17 itracanazole, 18 phytonadione, 19 5-methoxypsoralen. 20 The importance of physiologically relevant dissolution media in predicting the effect of food on the oral bioavailability of poorly soluble drugs has been emphasized in a recent review. 21 From the present study, it was clear that the inferior aqueous solubilities of 2 and 3 do not have as great an influence on their in vivo behavior, while their relative behavior in the presence of SIBLM reasonably predicted their in vivo behavior.…”

Section: Intravenous Administration Of Sodium Phenytoinsmentioning

confidence: 99%

Aqueous solubility and dissolution rate does not adequately predict in vivo performance: A probe utilizing some N‐acyloxymethyl phenytoin prodrugs

Stella

Rao

Martodihardjo

1999

Journal of Pharmaceutical Sciences

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Some physicochemical properties of N-acyloxyalkyl prodrugs of phenytoin were reported previously.(1,2) It was shown that despite their lower aqueous solubilities relative to phenytoin, these lower-melting prodrugs with apparently disrupted crystalline structures gave either comparable or enhanced in vitro solubility and dissolution rate in simulated intestinal media made up of bile salts and lecithin (SIBLM).(2) The current objective was to compare the in vivo behavior of two of these prodrugs to phenytoin in dogs and attempt to correlate the in vitro behavior to their in vivo behavior. The oral bioavailability of phenytoin after administration of phenytoin (1) and the selected prodrugs, 3-pentanoyloxymethyl 5, 5-diphenylhydantoin (2) and 3-octanoyloxymethyl 5, 5-diphenylhydantoin (3), in fed and fasted beagle dogs were compared to intravenously administered phenytoin. Phenytoin and its prodrugs showed improvement in fed-state phenytoin bioavailability relative to the fasted state indicating that food enhanced the delivery of phenytoin from phenytoin and its prodrugs. The increased bioavailability in the fed state may be due to stimulation of bile release by food and, for the prodrugs, possible catalysis of their dissolution by lipases.(3) In both, fasted and fed states, prodrugs 2 and 3 gave higher AUC values of phenytoin than the parent compound. The enhanced bioavailability of phenytoin after oral administration were more obvious in fed dogs. Although enhanced, AUC values of phenytoin from the prodrugs relative to phenytoin were not statistically different (at 95% confidence level) in fasted state, but were different in fed state. Although the aqueous solubilities and dissolution of both prodrugs were lower than phenytoin, dissolution of 2 and 3 was equivalent and greater, respectively, relative to phenytoin in SIBLM. As expected, the in vivo behavior correlated better with the in vitro SIBLM dissolution behavior. These results indicate that aqueous solubility per se does not adequately predict in vivo behavior.

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“…Synthetic 5 -methoxypsoralen (bergapten) and 5 -and 8 -methoxypsoralen ( 5 -MOP; 8 -MOP ; xanthotoxin or methoxsalen) are widely used in the treatment of several skin disorders including psoriasis, conditions of skin depigmentation (such as leprosy, vitiligio, and leucoderma), mycosis fungoides, polymorphous dermatitis, and eczema (Musajo and Rodighiero, 1962 ;Scott, Pathak and Mohm, 1976 ;Van Scott, 1976 ;Pathak and Fitzpatrick, 1992 ;Chadwick et al , 1994 ;Ehrsson et al , 1994 ). However, the psoralens have been linked to a higher incidence of skin cancer (Musajo and Rodighiero, 1962 ;Scott, Pathak and Mohm, 1976 ;Van Scott, 1976 ;Stern et al , 1979 ;Grekin and Epstein, 1981 ) and other disorders such as sister chromatid exchange, gene mutation, and chromosomal aberrations in humans (Calzavara -Pinton et al , 1994 ).…”

Section: Psoralensmentioning

confidence: 99%