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At least 19 recordsLinked to original sources

PubMed1994

Metabolic interactions of methoxsalen and coumarin in humans and mice.

Methoxsalen (8-methoxypsoralen) is a very potent inhibitor of human cytochrome P450 2A6 (CYP2A6) and mouse Cyp2a-5-mediated coumarin 7-hydroxylation in vitro. To determine the effect of methoxsalen on coumarin 7-hydroxylation in humans in vivo, five subjects were given 45 mg of methoxsalen and 5 mg of coumarin. Methoxsalen inhibited in vivo coumarin metabolism by 47 +/- 9.2% (mean +/- SEM). Methoxsalen was metabolized in human liver microsomes at the rate of 50-100 pmol/mg protein/min (approx. 30% of the activity in mouse liver microsomes). Metabolism was not inhibited by the anti-Cyp2a-5 antibody in human liver microsomes. NIH 3T3 cells stably expressing catalytically active CYP2A6 enzyme did not metabolize methoxsalen, indicating that CYP2A6 does not accept methoxsalen as a substrate. In pyrazole-induced mouse liver microsomes, methoxsalen metabolism was inhibited by the anti-Cyp2a-5 antibody. Cyp2a-5 protein expressed in the yeast Saccharomyces cerevisiae was capable of metabolizing methoxsalen, indicating that methoxsalen is a substrate of Cyp2a-5. Although kinetic studies indicated that the inhibition of coumarin 7-hydroxylation by methoxsalen is competitive in human liver microsomes, methoxsalen does not appear to be a substrate for CYP2A6. Methoxsalen and coumarin have the potential of strong metabolic interactions in man.

Animals↗

PubMed2006

Randomized, double-blind comparison of 1 mg/L versus 5 mg/L methoxsalen bath-PUVA therapy for chronic plaque-type psoriasis.

BACKGROUND: Bath-psoralen plus ultraviolet A (PUVA) radiation therapy is increasingly replacing oral PUVA because of its superior short- and long-term safety profile. Several investigations in recent years have led to a refinement of the bath-PUVA protocol; however, the optimal therapeutic concentration of methoxsalen in the bath water has as yet not been delineated. OBJECTIVES: The therapeutic efficacy and tolerability of bath-PUVA by using two different dilutions of methoxsalen (1 mg/L vs 5 mg/L or 0.0001% vs 0.0005%) were compared in 46 patients with chronic plaque-type psoriasis in a prospective, randomized, double-blind study. METHODS: Scores of the Psoriasis Area and Severity Index excluding psoriasis of the head (PASI(TUL)) and the Plaque Severity Index (PSI) were assessed at baseline and at biweekly intervals thereafter until (near)complete clearance or maximal improvement. In addition, methoxsalen plasma levels were determined immediately after the psoralen bath during the first week of treatment and treatment-related side effects were recorded throughout the entire study period. RESULTS: The median baseline PASI(TUL) score decreased from 11.7 (7.5-32.8) to 3.3 (0.6-1.2) (-72%) in the 1 mg/L methoxsalen group and from 10.8 (6.6-20.7) to 1.4 (03.2) (-87%) in the 5 mg/L methoxsalen group (P < .01). The median baseline PSI score decreased from 9 (6-12) to 3.1 (0.6-10) (-66%) in the 1 mg/L methoxsalen group and from 9.3 (7.3-12) to 1.6 (0-3.6) (-83%) in the 5 mg/L methoxsalen group (P < .01). The median cumulative UVA exposure dose was 25.4 (5.3-81.5) J/cm2 for 5 mg/L methoxsalen and 71.9 (20.7-587.3) J/cm2 for 1 mg/L methoxsalen (P = .001). The number of exposures (22 [11-29] vs 23 [11-34]) and treatment duration (43 [19-68] vs 44 [23-66] days) was comparable for both methoxsalen dilutions (P = .97). Median psoralen plasma levels were 0 (0-26) ng/mL after the 1 mg/L and 30 (0-64) ng/mL after the 5 mg/L methoxsalen immersion (P = .001). Mild to moderate adverse events were more common in the 5 mg/L methoxsalen group. LIMITATIONS: The conclusions of this randomized controlled study are limited by the relatively small sample size. CONCLUSIONS: Our data indicate that in bath-PUVA treatment the use of a high (5 mg/L) methoxsalen concentration is substantially more effective in clearing chronic plaque-type psoriasis than a low (1 mg/L) concentration.

Adult↗

PubMed2000

Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity.

Methoxsalen (8-methoxypsoralen) is an effective and selective mechanism-based inhibitor of human hepatic cytochrome P-450 (CYP)2A6 in vitro, and may have utility as a clinical probe for CYP2A6-catalyzed xenobiotic metabolism in humans in vivo. This investigation explored single-dose oral methoxsalen effects on human CYP2A6 activity in vivo, assessed by coumarin 7-hydroxylation. Eleven volunteers received 50 mg of oral coumarin on two occasions in a randomized crossover, 90 min after oral methoxsalen or nothing (controls). Plasma and urine 7-hydroxycoumarin and plasma methoxsalen concentrations were determined by HPLC. Methoxsalen pretreatment diminished area under the curve of plasma 7-hydroxycoumarin versus time by 24% (2.40 +/- 0.48 versus 3.20 +/- 0.55 microg. h. ml(-1); P <.001), and also decreased plasma 7-hydroxycoumarin C(max) (0.80 +/- 0.26 versus 1.4 +/- 0.5 microg/ml; P <.05); however, 7-hydroxycoumarin concentrations were only diminished 0.75 to 2 h after coumarin administration, but not thereafter. Methoxsalen diminished urine 7-hydroxycoumarin excretion in 0- to 1- and 1- to 2-h samples, but not thereafter, and total excretion was unchanged. Considerable individual variability in methoxsalen plasma concentrations was observed. There were significant correlations between the decrease in plasma 7-hydroxycoumarin C(max) and plasma methoxsalen C(max), but not between the decrease in plasma 7-hydroxycoumarin area under the curve and methoxsalen disposition. These results show that single-dose oral methoxsalen, in conventional doses, was a moderately effective inhibitor of human CYP2A6 activity in vivo, however, the duration of inhibition was limited. Interindividual variability in the extent of CYP2A6 inhibition appeared attributable to variability in the absorption and first-pass clearance of methoxsalen. Alternative doses, timing, and/or routes of methoxsalen administration are required for greater, longer, and more reproducible CYP2A6 inhibition than that provided by single-dose methoxsalen.

Administration, Oral↗

PubMed1989

Suicide inactivation of cytochrome P-450 by methoxsalen. Evidence for the covalent binding of a reactive intermediate to the protein moiety.

Incubation of rat liver microsomes with [3H]methoxsalen and NADPH resulted in the covalent binding of a methoxsalen intermediate to proteins comigrating with cytochromes P-450 UT-A, PB-B/D, ISF-G and PCN-E. Binding was increased by pretreatments with phenobarbital, beta-naphthoflavone (beta NF) and dexamethasone. Such pretreatments also increased the loss of CO-binding capacity either after administration of methoxsalen, or after incubation of hepatic microsomes with methoxsalen and NADPH. Immunoprecipitation of the methoxsalen metabolite-protein adducts in phenobarbital-induced microsomes was moderate with anti-UT-A antibodies, but marked with anti-PB-B/D and anti-PCN-E antibodies. Immunoprecipitation was observed also with anti-ISF-G (anti-beta NF-B) antibodies in beta NF-induced microsomes. Methoxsalen (0.25 mM) inhibited markedly the benzphetamine demethylase activity of phenobarbital-induced microsomes and the erythromycin demethylase activity of dexamethasone-induced microsomes. Whereas methoxsalen itself did not produce any binding spectrum, in contrast either in vivo administration of methoxsalen or incubation in vitro with methoxsalen and NADPH resulted in a low-to-high spin conversion of cytochrome P-450 as suggested by the appearance of a spectrum analogous to a type I binding spectrum. This low-to-high spin conversion was apparently due to a methoxsalen intermediate (probably, covalently bound to the protein and preventing partial sixth ligation of the iron). We conclude that suicide inactivation of cytochrome P-450 by methoxsalen is related to the covalent binding of a methoxsalen intermediate to the protein moiety of several cytochrome P-450 isoenzymes (including UT-A, PB-B/D, PCN-E as well as ISF-G and/or beta NF-B).

Animals↗

PubMed1987

Methoxsalen is a potent inhibitor of the metabolism of caffeine in humans.

The acute effect of a single oral dose of methoxsalen on the pharmacokinetics of caffeine was investigated in five nonsmoking volunteers with psoriasis. Caffeine, 200 mg orally, was administered to each subject at baseline before treatment with methoxsalen. One week later each subject was given a single oral dose of 1.2 mg/kg methoxsalen 1 hour before administrations of another oral dose of 200 mg caffeine. The clearance of caffeine declined markedly from 110 +/- 17 ml/min (mean +/- SE) in the control study to 34 +/- 5 ml/min after methoxsalen. During the period of maximum inhibition the mean elimination half-life of caffeine increased from 5.6 hours at baseline to 57 hours after administration of methoxsalen. The peak concentration of caffeine and the time to reach the peak concentration of caffeine were not affected by pretreatment with methoxsalen. Thus, methoxsalen, administered acutely, is a potent inhibitor of caffeine metabolism in humans with psoriasis. Results of this investigation suggest that the elimination of concurrently administered drugs may be inhibited in patients receiving methoxsalen. In comparison with other drugs, methoxsalen is the most potent inhibitor of drug metabolism in humans. Other work has shown that inhibition of drug metabolism by methoxsalen is associated with both extensive covalent binding of metabolite(s) of methoxsalen to liver microsomal protein in vitro and in vivo and inactivation of cytochrome P-450.

Adult↗

PubMedDate not supplied

Clinical pharmacokinetics of methoxsalen and other psoralens.

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.

5-Methoxypsoralen↗

PubMed1995

Suppression of cytochrome P450 (Cyp1a-1) induction in mouse hepatoma Hepa-1C1C7 cells by methoxsalen.

Cultured mouse hepatoma cell line Hepa-1c1c7 cells were treated with methoxsalen to assess the role of methoxsalen in the process of Cyp1a-1 induction. Treatment of Hepa-1c1c7 cultures with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced Cyp1a-1, as indicated by analysis of 7-ethoxyresorufin O-deethylation (EROD) activity and P4501A1 protein. When methoxsalen and TCDD were both added to cultures, TCDD-inducible EROD activity was greatly suppressed by methoxsalen in a dose-dependent manner. We find that treatment of Hepa-1c1c7 cells with methoxsalen inhibited CYP1A1 mRNA induction by TCDD as well as the concomitant increase P4501A1 protein. Formation of DNA-protein complexes between the dioxin receptor and its DRE target was inhibited by methoxsalen, as determined by gel mobility shift assays using oligonucleotides corresponding to DRE 3 of the Cyp1a-1 gene. These results suggest that the inhibitory action of methoxsalen on TCDD induction of the Cyp1a-1 gene expression in Hepa-1c1c7 cells might be antagonism of the DNA binding potential of nuclear dioxin receptor.

Animals↗

PubMed2003

The time course of topical PUVA erythema following 15- and 5-minute methoxsalen immersion.

BACKGROUND: Limited data exist in the literature concerning the characteristics of erythema following psoralen UV-A (PUVA) treatment using topical methoxsalen. To optimize the phototherapeutic regimen and reduce short- and long-term risks, knowledge of such basic information is essential. OBSERVATIONS: The characteristics of PUVA erythema following 15- and 5-minute immersion in methoxsalen was determined. The PUVA erythema after 15-minute methoxsalen immersion exhibited a broad peak, with the lowest median minimal phototoxic dose (MPD) at 96, 120, and 144 hours after UV-A irradiation. Seventy-three percent of subjects experienced peak erythema at 120 hours compared with only 45% at 72 hours. From the dose-response data, an increase in the erythema index of 0.025 (equivalent to the MPD) was significantly lower when determined at 120 hours after UV-A irradiation than at 72 hours (P =.03). The median maximum slope of the dose-response curve occurred at 144 hours. After 5-minute immersion, PUVA erythema displayed a broad peak from 72 hours. Erythema summation scores followed a trend similar to that of 15-minute immersion, but the intensity was significantly reduced. CONCLUSIONS: Methoxsalen-UV-A erythema exhibited a broad plateau between 96 and 144 hours, with most subjects at peak erythema at 120 hours. Reduction of methoxsalen immersion time significantly lowered the erythemal intensity. Minimum phototoxic dose reading at 72 hours underestimates the phototoxic effect of topical methoxsalen PUVA, and a change in the MPD assessment time should be considered.

Administration, Cutaneous↗

PubMedDate not supplied

The effect methoxsalene on hypnotic and subhypnotic doses of pentobarbital.

The effect of several doses of methoxsalen on hypnotic action of 40 mg/kg of pentobarbital in mice was studied. Methoxsalen was injected 30 minutes before the barbiturate. The highest methoxsalen dose of 22 mg/kg extended the duration of the hypnotic action of pentobarbital about 10 times compared to the control. The effect decreased with time, and 96 hours after this single dose of methoxsalen it was not significantly different from that observed with the control animals receiving only 40 mg/kg pentobarbital. The other methoxsalen doses (10, 5, and 2 mg/kg) exhibited an equal effect on the hypnotic action of pentobarbital, and only in the first measuring time. The effect could not be detected after 24 hours, and no dose dependence was observed. Small doses of methoxsalen of 2 and 1 mg/kg injected 30 minutes before a subhypnotic pentobarbital dose of 30 mg/kg produced sleep in 75% of animals of the both groups. In the control group, this dose produced no sleep in none of the animals.

Animals↗

PubMed1987

The drug methoxsalen, a suicide substrate for cytochrome P-450, decreases the metabolic activation, and prevents the hepatotoxicity, of carbon tetrachloride in mice.

Methoxsalen, a potent suicide inhibitor of cytochrome P-450 that can be used in humans, might be of value for the prevention of hepatitis in subjects with carbon tetrachloride poisoning. As a preliminary step, we have determined its effects on the hepatotoxicity of carbon tetrachloride in mice. Several monooxygenase activities, the in vitro covalent binding of carbon tetrachloride metabolites to microsomal proteins, and in vitro microsomal lipid peroxidation initiated by carbon tetrachloride metabolites were decreased by 60-90% in microsomes from mice killed 2 hr after the administration of methoxsalen (250 mumol X kg-1); microsomal lipid peroxidation mediated by endogenous iron and NADPH was not modified. Administration of methoxsalen (250 mumol X kg-1) 30 min before carbon tetrachloride (0.1 ml X kg-1) decreased both the in vivo formation of conjugated dienes in microsomal lipids and the in vivo covalent binding of carbon tetrachloride metabolites to lipids and proteins. This pretreatment completely prevented the hepatotoxicity of carbon tetrachloride. Other cytochrome P-450 inhibitors (cimetidine, SKF 525-A or piperonyl butoxide) given at this low molar dose (250 mumol X kg-1) exerted no protective effect. Methoxsalen (500 mumol X kg-1) was also effective, but only partially, when given 30 min after carbon tetrachloride (0.025 ml X kg-1). We conclude that pretreatment with methoxsalen decreases the metabolic activation of carbon tetrachloride, and completely prevents its hepatotoxicity in mice. Post-treatment with methoxsalen must be given early and is only partially effective in mice.

Alanine Transaminase↗

PubMed1996

Induction of rat hepatic cytochrome P4501A and P4502B by the methoxsalen.

The effect of methoxsalen, the inhibitor of the hepatic mixed function oxidase, on the expression of liver cytochrome P450s was examined in rats. Administration of methoxsalen to rats significantly increased the hepatic content of P450 and activities of microsomal ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), pentoxyresorufin O-dealkylase (PROD), a representative activity of P4501A1, P4501A2 and P4502B1/2, respectively, in a dose-dependent manner. In contrast, there was no effect on the P4502E1 catalyzed aniline hydroxylase. In the time-course experiment, methoxsalen exhibited a biphasic effect on EROD, MROD, and PROD activities, an initial inhibitory phase was followed by a phase of induction following a single treatment. Immunoblot analysis using anti-rat liver P4501A and P4502B revealed that increase in the apoprotein levels of P4501A1/2 and P4502B1/2 by methoxsalen was consistent with those in enzyme activity levels. Levels of mRNA of P4501A1/2 and P4502B1/2 were also increased by methoxsalen in Northern blot analysis. These results demonstrated that methoxsalen acts as an inducer of the hepatic microsomal mixed function oxidase; selective induction of P4501A and P4502B families involved increases in mRNA levels.

Aniline Hydroxylase↗

PubMed1986

Pre- or post-treatment with methoxsalen prevents the hepatotoxicity of acetaminophen in mice.

We have reported previously that methoxsalen is a suicide substrate for cytochrome P-450. We now report its effects on the metabolism and toxicity of acetaminophen in mice. Intragastric administration of methoxsalen (125 mumol X kg-1), 30 min before that of acetaminophen (600 mg X kg-1 i.p.), decreased the formation of the mercapturate and cysteine conjugates of acetaminophen, the depletion of glutathione and the in vivo covalent binding of an acetaminophen metabolite to hepatic proteins and prevented the increase in serum glutamic-pyruvic transaminase activity, the appearance of liver lesions and mortality. Methoxsalen (250 mumol X kg-1) also afforded complete protection when given intragastrically 2 hr after acetaminophen (600 mg X kg-1 i.p.). At that time, methoxsalen still decreased in vivo covalent binding measured per whole liver, and permitted a faster recovery of hepatic glutathione. Methoxsalen (180 mumol X kg-1) and N-acetylcysteine (919 mumol X kg-1) exerted additive protective effects when given concomitantly 2 hr after acetaminophen. We conclude that administration of methoxsalen decreases the metabolic activation and the hepatotoxicity of acetaminophen in mice.

Acetaminophen↗

PubMed1986

Inactivation of cytochrome P-450 by the drug methoxsalen.

Administration of methoxsalen (50 mumol X kg-1 i.p.) increased 4-fold the hexobarbital sleeping time in rats; at this low dose, SKF 525-A, piperonyl butoxide and cimetidine had little or no effect. In vitro, the concentration of methoxsalen inhibiting by 50% monooxygenase activities ranged from 10 microM (for benzo(a)-pyrene and hexobarbital hydroxylases] to 25 microM for 7-ethoxy-coumarin deethylase and aminopyrine demethylase); these values were in the range of those observed with SKF 525-A (1-50 microM) or piperonyl butoxide (10-100 microM) but much lower than those for cimetidine (100-500 microM). Methoxsalen (25-1000 microM) decreased cytochrome P-450 in vitro, in the presence of EDTA; this effect required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. Similarly, administration of methoxsalen (125 mumol X kg-1 i.p.) decreased cytochrome P-450 and monooxygenase activities in vivo; the decrease in cytochrome P-450 was enhanced by phenobarbital pretreatment and was prevented by piperonyl butoxide. There was no evidence for lipid peroxidation, denaturation into cytochrome P-420, formation of cytochrome P-450-metabolite complexes, destruction of heme or formation of green pigments. In contrast, a reactive metabolite of methoxsalen covalently bound to microsomal proteins; covalent binding required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. We conclude that methoxsalen is activated into a metabolite which destroys cytochrome P-450.

Animals↗

PubMed1987

Effects of methoxsalen on the metabolism of acetaminophen in humans.

We reported recently that the drug methoxsalen, a potent suicide inhibitor of hepatic cytochrome P-450, decreases the metabolic activation of acetaminophen and prevents its hepatotoxicity in mice. We have now studied the effects of methoxsalen on the metabolism of acetaminophen in humans. In vitro, 100 microM methoxsalen decreased by 40% the covalent binding of a [3H]acetaminophen metabolite to microsomal proteins after incubation of [3H]acetaminophen with human liver microsomes and an NADPH-generating system. In vivo, a single oral dose of methoxsalen (30 mg), given 3 hr before acetaminophen (1 g), decreased by 38% the partial apparent oral salivary clearance of acetaminophen into glutathione-derived conjugates (the end products of its oxidative metabolism) in nine human volunteers. These observations demonstrate that methoxsalen decreases the metabolic activation of acetaminophen in humans.

Acetaminophen↗

PubMed1987

Methoxsalen decreases the metabolic activation and prevents the hepatotoxicity and nephrotoxicity of chloroform in mice.

The effects of methoxsalen, a potent inhibitor of cytochrome P-450, on the hepatotoxicity and nephrotoxicity of chloroform have been determined in mice. Hepatic and renal monooxygenase activities and the in vitro covalent binding of chloroform metabolites to hepatic and renal microsomal proteins were decreased by 20-70% in microsomes from mice killed 2 hr after the administration of methoxsalen (250 mumol.kg-1ip) alone. Administration of methoxsalen (250 mumol.kg-1ip), 30 min before [14C]chloroform (1 ml.kg-1ip), did not modify blood levels of [14C]chloroform (and metabolites) but decreased the in vivo covalent binding of [14C]chloroform metabolites to hepatic and renal proteins 4 hr after the administration of [14C]chloroform. This pretreatment markedly decreased serum glutamic pyruvic transaminase activity, blood urea nitrogen, glucosuria, liver and kidney lesions, and mortality 24 hr after the administration of chloroform (0.125-1.5 ml.kg-1ip). Other cytochrome P-450 inhibitors (SKF 525-A or piperonyl butoxide), given at the same molar dose (250 mumol.kg-1ip), exerted no protective effect. Pretreatment with methoxsalen appears to decrease the metabolic activation of chloroform and essentially prevents its hepatotoxicity and nephrotoxicity in mice. Methoxsalen may have use as a tool to determine the role of metabolic activation by cytochrome P-450 in the hepatotoxicity and nephrotoxicity of drugs and chemicals.

7-Alkoxycoumarin O-Dealkylase↗

PubMed2003

The effect of methoxsalen on nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in vivo.

Nicotine is metabolized to the inactive metabolite cotinine by cytochrome P450 2A6. NNK, or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is a potent procarcinogen shown to be activated to a reactive mutagenic metabolite by the enzyme CYP2A6. We studied the effect of inhibiting CYP2A6 on smoking behavior and metabolism of the procarcinogen NNK. In study 1, abstinent smokers (n=7) received methoxsalen (a potent CYP2A6 inhibitor), 30-50 mg orally, one-half hour before three subcutaneous nicotine injections (31 microg/kg) were given at hourly intervals. Methoxsalen increased mean plasma nicotine by 47% (p<.01) and mean nicotine area under the curve (AUC) by 63% (p<.0001); and decreased nicotine clearance by 39% (p<.0001), relative to placebo. In study 2, smokers (n=11) were told to maintain their same number of cigarettes smoked while receiving methoxsalen, 10 mg orally three times daily for 3 days. On day 3 of methoxsalen treatment, a 29% increase in plasma nicotine/expired-air CO (an index of smoke exposure) (p=0.03) was observed. Urinary levels of trans 3'-hydroxycotinine (metabolized by CYP2A6 from cotinine) also were decreased (p<.0001), and significantly more NNK was metabolized to the inactive NNAL-glucuronide (1.04+/-0.54 pmol/mg on day 1 to 1.37+/-0.74 pmol/mg on day 4, p<.01) relative to placebo. Thus, treatment with the CYP2A6 inhibitor methoxsalen in vivo increases the routing of NNK to the inactive NNAL-glucuronide and decreases smoking. CYP2A6 inhibition may have potential as an exposure reduction or cessation strategy in tobacco dependence.

Administration, Oral↗

PubMed1979

Dermatological and ocular examinations in rabbits chronically photosensitized with methoxsalen.

Four groups of female Dutch-belted rabbits (Oryctulagus cuniculus) were given methoxsalen (12 mg/kg) or placebo by oral intubation and 1 hr later were exposed to UVA for either 2 or 8 hr. This procedure was repeated 5 days each week for 18 mo. A fifth group received no drug and no UVA exposure. The skin of the animals given methoxsalen and UVA showed signs of acute and chronic phototoxicity. Multiple peripheral blood parameters of hepatic, renal and hematologic function were normal and were not different between groups. Complete ophthalmoscopic examinations were performed periodically. No cataracts were seen in any of the animals. This data provides the perspective that in one species the daily dose of methoxsalen and UVA required to induce chronic cutaneous photosensitization is lower than the daily dose required to induce cataracts. It is inadvisable to interpret this data as suggesting that no risk exists for patients being treated with oral methoxsalen photochemotherapy. The experimental evidence supporting photosensitization as a cause of cataracts and implicating a role of lens DNA in this cataractogenesis is reviewed. Because methoxsalen-UVA alterations of lens DNA or protein could lead to delayed onset of cataracts, and because of the serious nature and potential preventability of phototoxic lens opacification, appropriate protective eye wear is recommended for all patients receiving oral psoralen photochemotherapy.

Animals↗

PubMed2001

Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro.

CYP2A6 is the principle enzyme metabolizing nicotine to its inactive metabolite cotinine. In this study, the selective probe reactions for each major cytochrome P450 (P450) were used to evaluate the specificity and selectivity of the CYP2A6 inhibitors methoxsalen, tranylcypromine, and tryptamine in cDNA-expressing and human liver microsomes. Phenacetin O-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), diclofenac 4'-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), 7-ethoxy-4-trifluoromethylcoumarin deethylation (CYP2B6), p-nitrophenol hydroxylation (CYP2E1), and omeprazole sulfonation (CYP3A4) were used as index reactions. Apparent K(i) values for inhibition of P450s' (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) activities showed that tranylcypromine, methoxsalen, and tryptamine have high specificity and relative selectivity for CYP2A6. In cDNA-expressing microsomes, tranylcypromine inhibited CYP2A6 (K(i) = 0.08 microM) with about 60- to 5000-fold greater potency relative to other P450s. Methoxsalen inhibited CYP2A6 (K(i) = 0.8 microM) with about 3.5- 94-fold greater potency than other P450s, except for CYP1A2 (K(i) = 0.2 microM). Tryptamine inhibited CYP2A6 (K(i) = 1.7 microM) with about 6.5- 213-fold greater potency relative to other P450s, except for CYP1A2 (K(i) = 1.7 microM). Similar results were also obtained with methoxsalen and tranylcypromine in human liver microsomes. R-(+)-Tranylcypromine, (+/-)-tranylcypromine, and S-(-)-tranylcypromine competitively inhibited CYP2A6-mediated metabolism of nicotine with apparent K(i) values of 0.05, 0.08, and 2.0 microM, respectively. Tranylcypromine [particularly R-(+) isomer], tryptamine, and methoxsalen are specific and relatively selective for CYP2A6 and may be useful in vivo to decrease smoking by inhibiting nicotine metabolism with a low risk of metabolic drug interactions.

Aryl Hydrocarbon Hydroxylases↗