OBJECTIVE: We assessed the effect of folic acid (FA) on the pharmacokinetics and pharmacodynamics of low-dose oral methotrexate (MTX) during the remission-induction phase of psoriasis treatment. METHODS: In a 32-week, open-label, two-way cross-over study, patients (n=20, seven men, aged 35-70 years) with moderate-to-severe plaque psoriasis were randomly assigned to receive MTX plus FA (20 mg/week) for 16 weeks followed by MTX monotherapy (three doses of MTX separated by 12-h intervals once a week) for an additional 16 weeks (treatment arm A, n=10) or to receive the opposite sequence of treatments (arm B, n=10). Dosing of MTX was individualised with the help of pre-study evaluation of plasma MTX pharmacokinetics. The Psoriasis Area and Severity Index (PASI), biochemistry and haematology tests and erythrocyte concentration of MTX polyglutamates (MTXPG) were evaluated throughout the study. RESULTS: In arms A and B, the mean (range) concentrations of MTXPG (nmol/L) were comparable [week 16: 96.2 (32.0-157) vs. 111 (73.7-175), P=0.32; week 32: 103 (55.8-173) vs. 83.6 (27.4-129), P=0.24]. After 16 weeks, the mean+/-SEM PASI decreased from 20.1+/-2.1 to 8.8+/-1.3 in arm A, while a greater reduction from 27.2+/-2.1 to 5.1+/-1.0 occurred in arm B (P<0.001). Positive correlations were found between the percent improvement in PASI at week 16 and the ratios of the concentration of MTXPG to plasma folate (rho=0.59, P=0.008) or RBC folate concentration (rho=0.56, P=0.013). Due to an accelerated decline in PASI in arm A and a trend to its worsening in arm B after crossing over of treatments, the mean absolute PASI scores in both arms were comparable at week 32. CONCLUSION: The antipsoriatic effect of MTX during the remission-induction phase of treatment is influenced by folate status and may be significantly less if combined treatment with FA is used, irrespective of pre-treatment folate levels. The individual tailoring of MTX dosing needs further attention because the mean percent PASI improvement from baseline was 83% and the inter-patient variability in response was low after 16 weeks of monotherapy with MTX.

• MeSH
• adherence pacienta MeSH
• antagonisté kyseliny listové škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• aplikace orální MeSH
• dermatologické látky škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• erytrocyty metabolismus   MeSH
• klinické křížové studie MeSH
• kyselina listová škodlivé účinky   krev   terapeutické užití   MeSH
• kyselina polyglutamová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• potravní doplňky MeSH
• psoriáza farmakoterapie   MeSH
• senioři MeSH
• vitaminy škodlivé účinky   krev   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté kyseliny listové MeSH
• dermatologické látky MeSH
• kyselina listová MeSH
• kyselina polyglutamová MeSH
• methotrexát MeSH
• vitaminy MeSH

Low dose pulse methotrexate (LDMTX) therapy has become effective in the treatment of autoimmune and lymphoproliferative diseases. The pharmacokinetics of LDMTX is individually highly variable, resulting in a different systemic exposure to the drug and a variable therapeutic/toxic effect in patients. The improvements and exacerbations of disease activity in relation to the introductions and discontinuations of LDMTX therapy suggest the possible immunosuppresive and anti-inflammatory properties of the drug. Because of a strong correlation between the drug pharmacokinetics and the therapeutic outcomes (pharmacodynamics), it seems to be possible to individualise the LDMTX therapy according to the results of pharmacokinetic/pharmacodynamic analysis. In the case of psoriasis, pharmacokinetic/pharmacodynamic analysis in our local study revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC(MTX) (area under the curve of methotrexate plasma concentrations; r(8) = -0.65, p < 0.001). The considerable inter-individual variability and low intra-individual variability in MTX pharmacokinetics, supports a role for therapeutic monitoring and dose individualisation at the start of pharmacotherapy. The results of this study suggest that a steady-state AUC(MTX) value of 700 nmol x h/L and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values. The preliminary results in our follow-up study suggest the statistically higher incidence of unwanted effects depending on maximum plasma concentration of the drug. Moreover, statistically significant correlation was found between the toxic effects and exposure to the drug regarding methotrexate plasma concentrations and intracellular storage in erythrocytes. However, the data are still in the process of being completed and are not yet published.

• MeSH
• antidota terapeutické užití   MeSH
• antimetabolity škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• intestinální absorpce MeSH
• kyselina listová terapeutické užití   MeSH
• leukovorin terapeutické užití   MeSH
• lidé MeSH
• methotrexát škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antidota MeSH
• antimetabolity MeSH
• kyselina listová MeSH
• leukovorin MeSH
• methotrexát MeSH