Molecular Basis for Pharmacokinetics and Pharmacodynamics of Methotrexate in Rheumatoid Arthritis Therapy

doi:10.2133/dmpk.DMPK-13-RV-119

Drug Metabolism and Pharmacokinetics

Volume 29, Issue 1, 2014, Pages 12-19

https://doi.org/10.2133/dmpk.DMPK-13-RV-119 Get rights and content

Summary:

Methotrexate (MTX) is a derivative of folic acid (folate) and commonly used as an anchor drug for the treatment of rheumatoid arthritis (RA). The pharmacokinetics (PK) and pharmacodynamics (PD) of MTX entirely depends on the function of specific transporters that belong to the two major superfamilies, solute carrier transporters and ATP-binding cassette transporters. Several transporters have been identified as being able to mediate the transport of MTX, and suggested to be involved in the disposition in the body and in the regulation of intracellular metabolism in target cells, together with several enzymes involved in folate metabolism. Thus, drug–drug interactions through the transporters and their genetic polymorphisms may alter the PK and PD of MTX, resulting in an interpatient variability of efficacy. This review summarizes the PK and PD of MTX, particularly in relation to RA therapy and focuses on the roles of transporters involved in PK and PD with the aim of facilitating an understanding of the molecular basis of the mechanism of MTX action to achieve its effective use in RA therapy.

References (100)

S. Chattopadhyay et al.
Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications
Mol. Cancer Ther.
(2007)
B.N. Cronstein
Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis
Pharmacol. Rev.
(2005)
J.W.G. Jacobs
Optimal use of non-biologic therapy in the treatment of rheumatoid arthritis
Rheumatology (Oxford)
(2012)
J.A. Singh et al.
2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis
Arthritis Care Res. (Hoboken)
(2012)
H. Yuasa et al.
Molecular and functional characteristics of proton-coupled folate transporter
J. Pharm. Sci.
(2009)
J. Braun et al.
Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial
Arthritis Rheum.
(2008)
K. Visser et al.
Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature
Ann. Rheum. Dis.
(2009)
R.A. Hamilton et al.
Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis
Br. J. Rheumatol.
(1997)
M. Hoekstra et al.
Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis
J. Rheumatol.
(2004)
D. Oguey et al.
Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis
Arthritis Rheum.
(1992)

P. Seideman et al.

The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis

Br. J. Clin. Pharmacol.

(1993)

M.A. Rochas et al.

Protein binding of methotrexate to human albumin and serum. A first derivative spectroscopic analysis

Arzneimittelforschung

(1991)

J.W. Paxton

Protein binding of methotrexate in sera from normal human beings: effect of drug concentration, pH, temperature, and storage

J. Pharmacol. Methods

(1981)

B. Bannwarth et al.

Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis

Clin. Pharmacokinet.

(1996)

R.A. Herman et al.

Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients

J. Pharm. Sci.

(1989)

B.A. Chabner et al.

Polyglutamation of methotrexate. Is methotrexate a prodrug?

J. Clin. Invest.

(1985)

J. Chladek et al.

Pharmacokinetics and pharmacodynamics of low-dose methotrexate in the treatment of psoriasis

Br. J. Clin. Pharmacol.

(2002)

B. Nuernberg et al.

Biliary elimination of low-dose methotrexate in humans

Arthritis Rheum.

(1990)

C.J. Allegra et al.

Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates

Proc. Natl. Acad. Sci. USA

(1985)

R.S. Funk et al.

Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line

J. Pharmacol. Exp. Ther.

(2013)

G. Haskó et al.

Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

Nat. Rev. Drug Discov.

(2008)

D. Cejka et al.

Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis

Arthritis Rheum.

(2010)

A.C. Racanelli et al.

Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition

Cancer Res.

(2009)

P. Lafforgue et al.

Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis

J. Rheumatol.

(1995)

M.I. Danila et al.

Measurement of erythrocyte methotrexate polyglutamate levels: ready for clinical use in rheumatoid arthritis?

Curr. Rheumatol. Rep.

(2010)

M. Da Costa et al.

The transport and accumulation of methotrexate in human erythrocytes

Cancer

(1981)

M.K. DeGorter et al.

Drug transporters in drug efficacy and toxicity

Annu. Rev. Pharmacol. Toxicol.

(2012)

F.M. Sirotnak et al.

Carrier-mediated membrane transport of folates in mammalian cells

Annu. Rev. Nutr.

(1999)

S.K. Desmoulin et al.

The human proton-coupled folate transporter: Biology and therapeutic applications to cancer

Cancer Biol. Ther.

(2012)

M. Shayeghi et al.

Identification of an intestinal heme transporter

Cell

(2005)

A. Qiu et al.

Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption

Cell

(2006)

D.T. Thwaites et al.

H⁺− coupled nutrient, micronutrient and drug transporters in the mammalian small intestine

Exp. Physiol.

(2007)

K. Inoue et al.

Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model

Am. J. Physiol. Gastrointest. Liver Physiol.

(2008)

Y. Nakai et al.

Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter

J. Pharmacol. Exp. Ther.

(2007)

N.K. Diop-Bove et al.

Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line

Mol. Cancer Ther.

(2009)

M. Furumiya et al.

Transcriptional regulation of PCFT by KLF4, HNF4α, CDX2 and C/EBPα: implication in its site-specific expression in the small intestine

Biochem. Biophys. Res. Commun.

(2013)

J.J. Eloranta et al.

Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter

Mol. Pharmacol.

(2009)

B.L. Urquhart et al.

The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs

Am. J. Physiol. Gastrointest. Liver Physiol.

(2010)

K.H. Dixon et al.

A novel cDNA restores reduced folate carrier activity and methotrexate sensitivity to transport deficient cells

J. Biol. Chem.

(1994)

R. Zhao et al.

Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs

J. Biol. Chem.

(2001)

R. Zhao et al.

Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells

Am. J. Physiol. Cell Physiol.

(2002)

R. Zhao et al.

Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors

Mol. Aspects Med.

(2013)

J.R. Whetstine et al.

The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identification of seven non-coding exons and characterization of a novel promoter

Biochem. J.

(2002)

Y. Wang et al.

Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis

Biochim. Biophys. Acta

(2001)

S.H. Min et al.

The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption

J. Pediatr.

(2008)

L.K. Stamp et al.

Expression of methotrexate transporters and metabolizing enzymes in rheumatoid synovial tissue

J. Rheumatol.

(2013)

A. Chango et al.

A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia

Mol. Genet. Metab.

(2000)

J.R. Whetstine et al.

Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers

Clin. Cancer Res.

(2001)

C. Laverdiere et al.

Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia

Blood

(2002)

T. Dervieux et al.

Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis

Pharmacogenetics

(2004)

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ReviewMolecular Basis for Pharmacokinetics and Pharmacodynamics of Methotrexate in Rheumatoid Arthritis Therapy

Summary:

Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications

Mol. Cancer Ther.

Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis

Pharmacol. Rev.

Optimal use of non-biologic therapy in the treatment of rheumatoid arthritis

Rheumatology (Oxford)

2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

Arthritis Care Res. (Hoboken)

Molecular and functional characteristics of proton-coupled folate transporter

J. Pharm. Sci.

Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial

Arthritis Rheum.

Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature

Ann. Rheum. Dis.

Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis

Br. J. Rheumatol.

Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis

J. Rheumatol.

Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis

Arthritis Rheum.

The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis

Br. J. Clin. Pharmacol.

Protein binding of methotrexate to human albumin and serum. A first derivative spectroscopic analysis

Arzneimittelforschung

Protein binding of methotrexate in sera from normal human beings: effect of drug concentration, pH, temperature, and storage

J. Pharmacol. Methods

Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis

Clin. Pharmacokinet.

Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients

J. Pharm. Sci.

Polyglutamation of methotrexate. Is methotrexate a prodrug?

J. Clin. Invest.

Pharmacokinetics and pharmacodynamics of low-dose methotrexate in the treatment of psoriasis

Br. J. Clin. Pharmacol.

Biliary elimination of low-dose methotrexate in humans

Arthritis Rheum.

Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates

Proc. Natl. Acad. Sci. USA

Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line

J. Pharmacol. Exp. Ther.

Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

Nat. Rev. Drug Discov.

Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis

Arthritis Rheum.

Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition

Cancer Res.

Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis

J. Rheumatol.

Measurement of erythrocyte methotrexate polyglutamate levels: ready for clinical use in rheumatoid arthritis?

Curr. Rheumatol. Rep.

The transport and accumulation of methotrexate in human erythrocytes

Cancer

Drug transporters in drug efficacy and toxicity

Annu. Rev. Pharmacol. Toxicol.

Carrier-mediated membrane transport of folates in mammalian cells

Annu. Rev. Nutr.

The human proton-coupled folate transporter: Biology and therapeutic applications to cancer

Cancer Biol. Ther.

Identification of an intestinal heme transporter

Cell

Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption

Cell

H+− coupled nutrient, micronutrient and drug transporters in the mammalian small intestine

Exp. Physiol.

Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model

Am. J. Physiol. Gastrointest. Liver Physiol.

Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter

J. Pharmacol. Exp. Ther.

Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line

Mol. Cancer Ther.

Transcriptional regulation of PCFT by KLF4, HNF4α, CDX2 and C/EBPα: implication in its site-specific expression in the small intestine

Biochem. Biophys. Res. Commun.

Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter

Mol. Pharmacol.

The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs

Am. J. Physiol. Gastrointest. Liver Physiol.

A novel cDNA restores reduced folate carrier activity and methotrexate sensitivity to transport deficient cells

J. Biol. Chem.

Review
Molecular Basis for Pharmacokinetics and Pharmacodynamics of Methotrexate in Rheumatoid Arthritis Therapy

H⁺− coupled nutrient, micronutrient and drug transporters in the mammalian small intestine