Re: MTX,Folic Acid. A little secret for you all

[Guest guest]

Hi All. When I first got PA I, like most I imagine, was in shock and went

through a definite grieving process. I'm now at the " Yeah? Well I don't give

a rat's " stage. Earlier on though, I was looking for answers everywhere.

What's the prognosis? MTX does what to my liver? Folic Acid? Milk Thistle?

Preparation H? You know what I mean. Well one of the best sites I found for

research and just a good read, was at:

http://www.biomednet.com/hmsbeagle

It's a site for science researchers. There's some great reading, but at the

bottom of the page you'll find a link to databases. Follow it, and then

Evaluated MEDLINE. You'll have to subscribe, but it's free. You might have

to streeeeeetch the truth a little. (They think I'm a scientist. Which is

partly true. I did undertake some in depth drug trials in my twenties.)

Anyway. Find your way through and your searches will find things like

this......

Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid

arthritis.

Bannwarth B, Péhourcq F, Schaeverbeke T, Dehais J

Clin Pharmacokinet 1996 Mar 30:3 194-210

Abstract

Low-dose pulse methotrexate has emerged as one of the most frequently used

slow-acting, symptom-modifying antirheumatic drugs in patients with

rheumatoid arthritis (RA) because of its favourable risk-benefit profile.

Methotrexate is a weak bicarboxylic acid structurally related to folic acid.

The most widely used methods for the analysis of methotrexate are

immunoassays, particularly fluorescence polarisation immunoassay. After oral

administration, the drug is rapidly but incompletely absorbed. Since food

does not significantly affect the bioavailability of oral methotrexate in

adult patients, the drug may be taken regardless of meals. There is a marked

interindividual variability in the extent of absorption of oral

methotrexate. Conversely, the intraindividual variability is moderate even

over a long time period. Intramuscular and subcutaneous injections of

methotrexate result in comparable pharmacokinetics, suggesting that these

routes of administration are interchangeable. A mean protein binding to

serum albumin of 42 to 57% is usually reported. Again, the unbound fraction

exhibits a large interindividual variability. The steady-state volume of

distribution is approximately 1 L/kg. Methotrexate distributes to

extravascular compartments, including synovial fluid, and to different

tissues, especially kidney, liver and joint tissues. Finally, the drug is

transported into cells, mainly by a carrier-mediated active transport

process. Methotrexate is partly oxidised by hepatic aldehyde oxidase to

7-hydroxymethotrexate. This main, circulating metabolite is over 90% bound

to serum albumin. Both methotrexate and 7-hydroxy-methotrexate may be

converted to polyglutamyl derivatives which are selectively retained in

cells. Methotrexate is mainly excreted by the kidney as intact drug

regardless of the route of administration. The drug is filtered by the

glomeruli, and then undergoes both secretion and reabsorption processes

within the tubule. These processes are differentially saturable, resulting

in possible nonlinear elimination pharmacokinetics. The usually reported

mean values for the elimination half-life and the total body clearance of

methotrexate are 5 to 8 hours and 4.8 to 7.8 L/h, respectively. A positive

correlation between methotrexate clearance and creatinine clearance has been

found by some authors. Finally, the pharmacokinetics of low-dose

methotrexate appears to be highly variable and largely unpredictable even in

patients with normal renal and hepatic function. Furthermore, studies in

patients with juvenile rheumatoid arthritis provide evidence of

age-dependent pharmacokinetics of the drug. These features must be

considered when judging the individual clinical response to methotrexate

therapy. Various drugs currently used in RA may interact with methotrexate.

Aspirin might affect methotrexate disposition to a greater extent than other

nonsteroidal anti-inflammatory drugs without causing greater toxicity.

Corticosteroids do not interfere with the pharmacokinetics of methotrexate,

whereas chloroquine may reduce the gastrointestinal absorption of the drug.

Folates, especially folic acid, have been shown to reduce the adverse

effects of methotrexate without compromising its efficacy in RA. Finally,

both trimethoprim-sulfamethoxazole (cotrimoxazole) and probenecid lead to

increased toxicity of methotrexate, and hence should be avoided in patients

receiving these drugs. A relationship between oral dosage and efficacy has

been found in the range 5 to 20mg methotrexate weekly. The plateau of

efficacy is attained at approximately 10 mg/m2/week in most patients. No

clear relationship between pharmacokinetic parameters and clinical response

has been demonstrated. Overall, the dosage must be individualised because of

interindividual variability in the dose-response curve. This variability is

probably related, at least in part, to the wide interindividual variability

in the disposition of the drug.

Congrats if you're still with me here, .