Pharmacokinetics of methotrexate in continuous ambulatory peritoneal dialysis

Abstract

The pharmacokinetics of methotrexate and its 7-hydroxy metabolite were studied in a patient undergoing continuous ambulatory peritoneal dialysis. A biphasic plasma-disappearance pattern of methotrexate was observed, with half-lives of 3.5 and 29 hours. The 7-hydroxy metabolite accumulated and showed a very slow rate of elimination, with an estimated final elimination half-life of over 120 hours. The mean peritoneal clearance rate of methotrexate was 0.13 l/h (range 0.05-0.20 l/h), dwell times significantly influenced the clearance rate. Strict monitoring of the methotrexate level, even after low doses, is necessary in continuous ambulatory peritoneal dialysis patients, to prevent serious bone marrow toxicity.

Extracorporeal Treatment for Methotrexate Poisoning

“…A total of 1376 articles were identified after removal of duplicates. In the final analysis, 92 articles were included, including two in vitro experiments (174,175), four animal experiments (176 –179), 84 case reports and case series (24,35,88,90,126,163,170,171,180 –255), one pharmacokinetic modeling study (256), and one observational study (160). Although several articles were designed as pharmacokinetic studies in kidney failure patients (170,190,204,225,242), many participants in these studies developed methotrexate-associated toxicity and were included in case reports.…”

“…This was confirmed in all studies in which both glucarpidase and extracorporeal treatments were given (58,171,210,213,217,224,227,238,245,247). Some reports noted that dialysis clearance is concentration dependent (190,195,238,244), although this is surprising in the absence of saturation of protein binding or membrane adsorption; this may have been caused by detection sensitivity of the assay at low concentration, or redistribution of methotrexate from red blood cells in the outlet, inflating that methotrexate concentration. Addition of albumin to the dialysate increased CKRT clearance by 20% at most, with massive increase in cost (218,227).…”

“…Many complications were reported, although it is unclear if some were related to the procedure, methotrexate, underlying disease, or comorbidities. Complications include hypotension during hemodialysis requiring switch to CKRT (252,254), myocardial infarction and ventricular tachycardia (243), hypokalemia and hypophosphatemia (213), cardiac arrest (186), abdominal pain and loss of consciousness that required termination of hemoperfusion (163), thrombocytopenia and/or leucopenia (mostly related to hemoperfusion) (163,190,191,195,199,208,212), and bleeding from catheter site (191). Because of baseline immunosuppression and cytopenia and because multiple extracorporeal sessions are often performed, the risk of catheter infection is higher (225).…”

Systemic methotrexate therapy for psoriasis: past, present and future

“…Around 50% of MTX is bound to plasma protein, and may be displaced by other drugs, including salicylates, tetracycline and phenytoin. Because MTX is cleared primarily by proximal tubular filtration, significant renal insufficiency can lead to reduction in overall MTX clearance from 84.6 to 2.8 mL/min/m 2 , and hence will require a dose adjustment to minimize toxicity . At the pharmacogenetic level, it has been found that polymorphisms in the dihydrofolate reductase (DHFR) are associated with MTX efficacy, although the results of various studies are not uniformly consistent .…”

“…Because MTX is cleared primarily by proximal tubular filtration, significant renal insufficiency can lead to reduction in overall MTX clearance from 84.6 to 2.8 mL/min/m 2 , and hence will require a dose adjustment to minimize toxicity. 10,11 At the pharmacogenetic level, it has been found that polymorphisms in the dihydrofolate reductase (DHFR) are associated with MTX efficacy, although the results of various studies are not uniformly consistent. 12 The relative resistance to the effect of MTX has also been ascribed to impaired transport of MTX into cells, 13 decreased ability to synthesize MTX polyglutamate (MTX-PG), 14 and increased expression of drug efflux transporters of the multidrug resistance protein class.…”