Effect of oral 8-methoxypsoralen on rat liver microsomal cytochrome P-450

Tsambaos, D.; Vizethum, W.; Goerz, G.

doi:10.1007/bf00446951

Cited by 8 publications

(3 citation statements)

References 16 publications

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“…Under these conditions ethanol showed a strong inducing effect on metabolism. In a normal dose of 0.6 mg/kg/day methoxsalen had no effect on rat liver cytochrome P-4S0 activity and content, but following a 10-to 20-fold dose increase the specific activity, but not the content, of this enzyme in rat liver was increased (Tsamboas et al 1978).…”

Section: Metabolismmentioning

confidence: 96%

Clinical Pharmacokinetics of Methoxsalen and Other Psoralens

Wolff

Thomas

1986

Clinical Pharmacokinetics

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The psoralen derivative methoxsalen and to a lesser extent some other furocoumarin congeners, including bergapten and trioxsalen, have acquired a place in the treatment of psoriasis and other dermatoses. They are inactive after oral or topical administration unless combined with irradiation with long-wave ultraviolet light (UVA). This combination is referred to as photochemotherapy or PUVA (psoralen plus UVA). Usually a standard dose of methoxsalen (0.5 to 0.7 mg/kg) is given 2 hours prior to irradiation, and the light dose is assessed individually. Differences in response are often due to the unpredictable pharmacokinetic behaviour of the drug. Reversed-phase high-performance liquid chromatography is the method of choice for determining methoxsalen concentrations in body fluids, but gas chromatography with electron capture detection and thin-layer chromatography with fluorescence densitometry also give favourable results. The absorption of methoxsalen, and hence clinical response, is affected by concomitant food ingestion and by differences in drug formulation. A liquid preparation in soft gelatin capsules or a microenema give higher and more rapidly appearing maximum serum concentrations (Cmax) than crystalline methoxsalen in tablets or capsules. With a standard dose of tablets, Cmax is in the range of 50 to 250 micrograms/L and appears between 1 and 2 hours after ingestion. The drug has a high, but variable, intrinsic metabolic clearance and is almost completely metabolised. Serum elimination half-life is in the order of 0.5 to 2 hours. There is a large interpatient variability in the clearance of methoxsalen (40 to 650 L/h); the relative distribution volume ranges between 1 and 9 L/kg. Concentrations in suction blister fluid (sbf) are approximately one-third of Cmax in serum and remain relatively constant as long as the plasma concentration exceeds the suction blister fluid level. Individuals with a high methoxsalen clearance and low Cmax usually show less biological sensitivity to PUVA (in terms of minimal phototoxic dose of UVA) than low-clearance patients and frequently a less favourable clinical response. Hence Cmax can be used for the purpose of therapeutic drug monitoring and, in practice, this may be determined by measuring serum concentrations at least at 1, 2, and 3 hours after ingestion. Bergapten is somewhat less active than methoxsalen but has similar pharmacokinetic characteristics. The bioavailability of trioxsalen is poor after oral intake and this drug is mainly administered topically.

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Section: Metabolismmentioning

confidence: 96%

Clinical Pharmacokinetics of Methoxsalen and Other Psoralens

Wolff

Thomas

1986

Clinical Pharmacokinetics

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“…Xanthotoxin (7) was reportedly a potent inhibitor of the in vivo phase I metabolism of phenytoin, hexobarbital, caffeine, and theophylline (16,17). This furanocoumarin (7) was also found to be an inducer of hepatic BCD, AHH, and ethylmorphine deethylase, when administered orally to rats at relatively low doses over several days (18,19). Recently, it has been demonstrated that xanthotoxin (7) can be metabolically activated to intermediates that bind covalently to liver microsomal protein and that the bioactivation of xanthotoxin (7) led to the inactivation of cytochrome P450 through covalent modification of the apoprotein (14,20,21).…”

Section: Introductionmentioning

confidence: 99%

Inhibition and inactivation of murine hepatic ethoxy- and pentoxyresorufin O-dealkylase by naturally occurring coumarins

Cai

Bennett

Nair

et al. 1993

Chem. Res. Toxicol.

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The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.

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“…8) Several bioactivities have been reported for methoxsalen, including modulation of biotransformation enzymes (e.g., cytochromes P450). 9) However, relatively little is known regarding the effects of methoxsalen on AchE and cognition. The purpose of the present study was to assess the inhibitory activity of methoxsalen against AchE from the rat pheochromocytoma cell line (PC12 cells) and to determine whether it would enhance memory in trimethyltin chloride (TMT)-treated amnesic mice.…”

mentioning

confidence: 99%