The pharmacology of methotrexate Elise A. Olsen, MD Durham, North Carolina Methotrexate is a useful antimetabolite for the treatment of both benign and malignant proliferative disorders. When the pharmacokinetics and potential toxicity of this drug are understood, treatment regimens can be tailored to the underlying kinetics of the target pop-ulation. With the appropriate knowledge of the importance of urinary excretion of methotrexate and factors that influence this and with the ready availability of leucovorin, toxicity can be avoided in all but the most unusual of circumstances. (J AM ACAD DERMATaL 1991;25:306-18.)

The antiproliferative effect of the folic acid antagonist methotrexate has been clinically exploited in the treatment of malignancy since 1953 1 and in the treatment of psoriasis since 1958. 2 Methotrexate is the systemic chemotherapeutic agent most com~ monly used by dermatologists to treat not only psoriasis but also pityriasis rubra pilaris,3 sarcoid,4-6 dermatomyositis, 7 and lymphoproliferative diseases including pityriasis lichenoides et varioliformis acuta,8 lymphomatoid papulosis,9-11 and cutaneous T cell lymphoma. 12, 13 The clinical efficacy and toxicities of methotrexate can be predicted and/or prevented by understanding the basic cellular and pharmacokinetic properties of the drug. As the potential uses for methotrexate in the dermatologic realm expand, and as our experience with a wider variety of doses and routes broadens, dermatologists need to become familiar with the complexities of this remarkable, but potentially lethal, drug. This article reviews the pharmacology of methotrexate and the folic acid analog and methotrexate antagonist leucovorinand offers general guidelines for the safe, effective use of methotrexate.

MECHANISM OF ACTION Folate vitamins are a class of essential cofactors that share a common structure (Fig. I) with three basic component parts: a pteridine nucleus, paminobenzoic acid, and glutamic acid. Folates serve a common function, mainly the transfer of oneFrom the Division of Dermatology, Department of Medicine, Duke University Medical Center. Reprint requests: Elise A. Olsen, MD, Box 3294, Duke University Medical Center, Durham, NC 27710

16/1/29453

306

carbon groups, which is accomplished only through the reduction of the pteridine ring at positions 5, 6, 7, and 8, a reaction carried out by the cytoplasmic enzyme dihydrofolate reductase (Fig. 2).14 A dihydrofolate, or [FH2 ], thus becomes a fully reduced tetrahydrofolate, or [FH4]. Single carbon fragments are added enzymatically to the resulting tetrahydrofolate [FH4] in various configurations and may then be transferred in specific synthetic reactions (Fig. 3). The major physiologic circulating folate, NSmethyl [FH4], is absorbed directly through the gastrointestinal tract but can be rapidly formed in the plasma by metabolism of folic acid (pteroglutamic acid) or .N5-formyl [FH4], also called leucovorin, folinic acid, or citrovorum factor. In the normal adult, the minimal daily requirement of folate has been estimated at 50 /-Lg, whereas the pregnant or lactating women and patients with high rates of cell turnover may require as much as 100 to 200 p,g or more per day.15 Methotrexate or amethopterin, an analog of folic acid, is a weak bicarboxylic organic acid, molecular weight of 454 daltons, negatively charged at neutral pH and with limited lipid solubility.14, 16 In general, methotrexate is actively transported into cells except at high concentrations (> 10 /-LmoljL) when active transport mechanisms may be saturated and passive diffusion predominates. 17 Once intracellular, methotrexate competitively binds to dihydrofolate reductase (Fig. 4). This reaction is critical to cell reproduction because dihydrofolate reductase (DHFR) is the only enzyme able to catalyze the conversion of [FH 2 ] to the active [FH4] form. 14 A continually renewed supply of NS· 1°-methylene [FH4] is a necessary cofactor that provides single carbon fragments

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Pharmacology of methotrexate 307

pteridine ring

para-aminobenzoic acid

glutamyl residue( s)

Folic acid (pteroylglutamic acid; R1 =OH, R2= H Methotrexate (4-amino-N10 -methyl pterylglutamic acid; R1 =NH 2, R2 = CH 3

)

Fig. 1. Structure of folic acid and methotrexate. for thymidyate synthetase to convert 2-deoxyuridylate to thymidylate. 14, 18 Without thymidylate, DNA synthesis ceases. Thus methotrexate has been said to be an S-phase-specific chemotherapy. Methotrexate may also have broader effects on RNA and protein synthesis because NI0-formyl [FH4] is necessary for the biosynthesis of inosinic acid and precursor purines.14, 16 Reduced folates are also necessary cofactors for the conversion of serine to glycine and homocysteine to methionine, and thus provide additional mechanisms for disruption of protein synthesis. 16 Methotrexate, and folates in general, are metabolized intracellularly to polyglutamates by folyl polyglutamate synthetase. 18 Folate-polyglutamates are preferentially retained intracellularly and function as cofactors that are more efficient than the uniglutamate folates. Methotrexate-polyglutamate is also preferentially retained in cells and allows accumulation ofthe free intracellular drug at levels far above what could be achieved if the drug were in equilibrium with the extracellular concentration. 14 Methotrexate-polyglutamate has equal affinity with methotrexate for DHFR but dissociates at a slower rate 14 and crosses cellular membranes less easily.18 The longer the chain length of polyglutamates, the longer the intracellular retention and hence the duration of suppression of DNA synthesis. The degree of glutamination is dependent on both methotrexate concentration and the duration of methotrexate exposure. Methotrexate-polyglutamate also affects other folate-requiring enzymes not directly affected by methotrexate, including thymidylate synthase and aminoimidazole carboxamide ribonucleotide transformylase; blockage of the latter enzyme activities affects de novo purine synthesis. 14 By competitive binding of the enzyme pteroylglutamyl conjugase,

the synthesis of pteroyl polyglutamates is reduced and leads to intracellular folate depletion,19 There appears to be a separate carrier-mediated mechanism for the cellular efflux of methotrexate that is sensitive to sodium azide and vincristine. 16

ABSORPTION, METABOLISM, EXCRETION Interpatient differences in the rate and amount of absorption of oral methotrexate are considerable. 14, 20 In addition, there is a dose-dependent and saturable intestinal absorption; in cancer patients at doses of less than 30 mg/m 2, methotrexate is nearly completely absorbed from the gastrointestinal tract,16, 21 whereas at 50 mg/m 2, 20% to 50% is absorbed, and at 200 mg/m 2, 25% is absorbed. 14 However, there is evidence that absorption may not be complete even at low doses of methotrexate; oral doses of O. 3mg/kg given to adult psoriasis patients22 and 6.3 to 28.1 mg/m 2 given to children with acute lymphocytic leukemia or dermatomyositis 23 resulted in absorption of 32% to 98% and 23% to 95% of the methotrexate dose, respectively. Two patterns of absorption, fast and slow, can occur, with a suggestion that prolonged administration of oral methotrexate can lead to slower absorption. 24 Food decreases methotrexate absorption,17 as do nonabsorbable antibiotics; the latter suggests methotrexate metabolism by intestinal bacteria. 16 Because methotrexate is a highly polar molecule, it is unlikely that absorption from the intestine is by passive diffusion but more likely by the folate-active transport . pathway.25 The absorption of methotrexate after intramuscular administration appears to be rapid and complete with peak levels achieved at approximately 2 hours after injection. 20, 26 However, large interindividual variations can be observed in the pharmacokinetics of methotrexate even after intravenous

Journal of the American Academy of Dermatology

308 Olsen

Tetrahydrofolate

2

..I

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Fig. 2. One-carbon fragments carried by tetrahydrofolate.

dosing. 21 Methotrexate demonstrates age-dependent pharmacokinetics; there is greater distribution and elimination of the drug in younger patients after intravenous injection. 27 There is a triphasic disappearance of methotrexate; the initial half-life of 0.75 hour is probably secondary to drug distribution, the second phase of 2 to 3.5 hours probably reflects renal clearance, and the terminal half-life of 10.4 hours most likely is secondary to the enterohepatic circulation. 16 The latter begins when the plasma concentration of methotrexate is approximately 0.1 ~mol/L or 10-7 mol/L.18,28 Distribution into the iq.t'erstitial fluids occurs slowly and pathologic increases, as in ascites or pleural effusions, may act as reservoirs that prolong methotrexate levels. 16 Diffusion ·into the central nervous system (CNS) from plasma is low, secondary to methotrexate's limited lipid solubility. During constant intravenous infusion, CE?F concentrations of methotrexate are 3% of plasma levels and lead to a 30: 1 steady-state gradient between plasma and CSF.14 However, doses of methotrexate of 1 gm/m 2 or more are able to achieve therapeutic concentrations (1 X 10-6 mQI/L) in the CSF.29. 30 Conversely, methotrexate by the intrathecal route easily achieves suprapharmacologic doses. Intrathecal methotrexate exits through the CSF either by bulk fl9W through the arachnoid granulations,31 by passive absorption of CSF from extracellular fluid into the capillaries of the brain and spinal cord, or by active transport through the choroid plexus epithelhim;32 the latter

can be inhibited by elevated intracranial pressure or probenecid. Intrathecal methotrexate can lead to prolonged· plasma levels of methotrexate through this egress and lead to potential systemic toxicity; 10 to 15 mg/m 2 of methotrexate given intrathecally generates more than 10-8 mol/L plasma levels two to three times longer than if the methotrexate were given intravenously.16 Fifty percent to 70% of methotrexate is protein bound, especially to albumin. 16 Concomitant drugs that decrease methotrexate plasma protein binding either by competitive displacement of methotrexate from albumin binding sites or by altering albumin's binding affinity for methotrexate, such as salicylates, tetracycline, probenecid, chloramphenicol, phenytoin, and sulfonamides, may increase free methotrexate.I 6, 18 Fifty percent to 90% (the higher percentage with lower doses) of methotrexate is excreted in the urine unchanged within 24 hours by renal filtration, secretion, and concentration-dependent tubular resorption. 16. 18. 27 The tubular reabsorption process becomes saturated at plasma concentrations of 0.5 to 0.8 ,ug/ml (well within the range achievable with psoriatic doses ofmethotrexate) and results in increased renal methotrexate clearance33 until the tubular secretion mechanism is saturated at the extracellular methotrexate concentration of 10-4mol/L.34 Weak organic acids, such as probenecid, aspirifi, p-aminohippuric acid, phenylbutazone, penicillin, ascorbic acid, and sulfonamides,17, 35 decrease renal tubular transport and may prolong ex-

Volume 25 Number 2, Part 1 August \99\

Pharmacology of methotrexate 309

SH

I

CH2

I

CH 2

I

H-C-NHi

I coo'

Homoey:llielha

l~

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CH 3

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Fig. 3. Example of one~carbon fragment exchanges with tetrahydrofolates. DHFR, Dihydrofolate reductase; (GluJm glutamic acid or polyglutamates. cretion. Methotrexate toxicity has also occurred with concomitant use of nonsteroidal antiinflammatory drugs, including ketoprofen, naproxen, indomethacin, dic1ofenac, and azapropazone. 36-39 The solubility of methotrexate in urine is directly proportional to the urine pH: methotrexate will precipitate in acid urine at concentrations of 2 X 10- 3 mol/L or greater, but at pH 7, solubility is tenfold greater, 16 Alkalinization also ionizes the drug within the tubule, which retards its reabsorption and promotes its clearance,16 Fecal excretion after oral methotrexate is proportional to the drug absorbed, Fecal excretion after intravenous methotrexate is only 1% to 2%; most methotrexate excreted in the bile is reabsorbed in the intestinal mucosa. 16 Nonabsorbable oral antibiotics may interfere with this enterohepatic circu1ation. 35 The amount of methotrexate metabolites formed after intravenous administration is 6% of the dose. 21 The predominant metabolite is 7-hydroxymethotrexate formed by the hepatic enzyme aldehyde oxidase during the terminal phase of methotrexate elimination. 16 7-Hydroxymethotrexate is four times less soluble in acid urine than methotrexate and thus may contribute to nephropathy, particularly at high doses,16, 40 After oral administration, approximately 35% of the absorbed dose is excreted as metabolites,2\ During enterohepatic cycling, a pteroate derivative is formed, possibly derived from

bowel bacteria that have hydrolyzed the terminal glutamate from methotrexate,21, 28 This pteroate metabolite is 200 times less potent than methotrexate in inhibiting dihydrofolate reductase. 21 DOSES

The dose and route of methotrexate given for a particular indication depend on the kinetics of the target population with an optimal methotrexate concentration for each responsive neoplasm,41 Obviously, rapidly growing cells, both normal and diseased, are vulnerable to the effects of an S-phasespecific therapy, Thus the goal of treatment with methotrexate is minimal toxicity to endogenous healthy tissue but control or eradication of the aberrant hyperproliferative state. Oral methotrexate in doses of more than 20 mg/m2 is a relatively safe, effective dose for benign proliferative conditions, such as psoriasis, for several reasons. With optimal absorption of a single 20 mg/m 2 dose, peak methotrexate blood levels of llLmol/L are reached 1to 5 hours after oral dosing; levels remain greater than 0.1 ILmol/L approximately 6 hours, 14 The therapeutic concentration for methotrexate is deemed to be 10- 6 mol/L or greater, 14, 42 In general, inhibition of DNA synthesis ceases at levels less than 10- 8 molJL and inhibition of protein synthesis at less than 10-7 mol/L.14 At these levels, the concentration of methotrexate in the urine is unlikely to lead to precipita-

310

Journal of the American Academy of Dermatology

Olsen

~

N10 formyl - [FH 4 ](Glu)n

---------~)

purine synthesis

~.

N5' 1O "0.me,!y,.[FH'l2000 cGy)84; it is hypothesized that the radiation may increase vascular premeability and contribute to toxicity. Biopsy specimens in these cases show diffuse multifocal coagulates of necrosis, demyelination, and axonal swelling of the white matter. Eye Ocular burning and pruritus 2 to 7 days after high-dose methotrexate (30 to 250 mg/kg) has been reported. 85 Ophthalmologic examination was normal except for decreased tearing; no inflammation was noted. Concentration of methotrexate in tears approximated plasma levels and remained more than 1O~8 mol/L for 48 hours; this suggests a direct methotrexate toxicity. This was unassociated with systemic toxicity or nephrotoxicity and generally resolved in a few days.85 Methotrexate in pregnancy Methotrexate is a known teratogen 18 and may cause oligospermia. 86 Although methotrexate is not a mutagen,28 current recommendations are that both women and men take measures to avoid either becoming pregnant or impregnating their partner during therapy and for 12 weeks after discontinuation of methotrexate. 43 , 87 Miscellaneous effects There is no evidence that methotrexate is a carcinogen. 28 , 43, 88 There is even some question whether methotrexate is an immunosuppressive agent. In one study, cell-mediated immunity as

316

Olsen

measured by reactivity to DNFB was markedly re~ duced compared with controls,43 and in another, antibody synthesis was temporarily suppressed with high-dose methotrexate. 89 Low weekly doses of methotrexate such as those used in psoriasis and rheumatoid arthritis do not appear to affect adversely humoral or cellular immunity.55.90 Methotrexate inhibits the in vitro response of polymorphonuclear cells to chemotactic agents and decreases chemotactic migration in psoriasis patients. 91 ,92 Recently, van de Kerkhof92 showed a strongly decreased leukotriene B 4-induced intraepidermal penetration of polymorphonuclear cells in psoriasis patients who were receiving methotrexate. Whether the latter effects contribute to the mechanism of response in psoriasis is still speculative. One child who had been taking daily methotrexate for 255 days developed bony osteoporosis and severe scoliosis. 93 Fever to 102 0 F during the first few days after high-dose methotrexate infusion without signs of infection has also been reported. 94 REFERENCES 1. Van Scott EJ, Auerbach R, Weinstein GD. Parenteral methotrexate in psoriasis. Arch Dermatol 1964;89:550-6. 2. Edmundson WF, Guy WB. Treatment of psoriasis with folic acid antagonists. Arch DermatoI1958;78:200-3. 3. Knowles WR, Chernosky ME. Pityriasis rubra pilaris: prolonged treatment with methotrexate. Arch Dermatol1970; 102:603-12. 4. Veien NK. Cutaneous sarcoidosis: prognosis and treatment. Clin Dermatol 1986;4:75-87. 5. Toews G B, Lynch JP III. Methotrexate in sarcoidosis. Am J Med Sci 1990;300:33-6. 6. Webster GF, Razsi LK, Sanchez M, et al. Methotrexate therapy in cutaneous sarcoidosis [Letter]. Ann Intern Med 1989;111 :538-9. 7. Clements PJ, Davis J. Cytotoxic drugs: their clinical application to the rheumatic diseases. Semin Arthritis Rheum 1986; 15:231-54. 8. Cornelison RL Jr, Knox JM, Everett MA. Methotrexate for the treatment of Mucha-Habermann disease. Arch DermatoI1972;106:507-8. 9. Lange WG, Thomsen K. Methotrexate in lymphomatoid papulosis. Br J Dermatol 1984; 111 :93-5. 10. Lynch PJ, Saied NK. Methotrexate treatment of pityriasis lichenoides and lymphomatoid papulosis. Cutis 1979;23: 634-6. 11. Thomsen K, Wantzin GL. Lymphomatoid papulosis. J AM ACAD DERMATOL 1987;17:632-6. 12. Zackheim HS, Epstein EH Jr. Low-dose methotrexate for the Sezary syndrome. J AM ACAD DERMATOL 1989;21: 757-62. 13. McDonald CJ, Bertino JR. Treatment of mycosis fungoides lymphoma: effectiveness of infusions of methotrexate followed by oral citrovorum factor. Cancer Treat Rep 1978;62:1009-14. 14. Jolivet J, Cowan KH, Curt GA, et al. The pharmacology and clinical use of methotrexate. N Engl J Med 1983;309; 1094·104.

Journal of the American Academy of Dermatology

15. Hillman RS. Vitamin B 12, folic acid, and the treatment of megaloblastic anemias. In: Gilman AG, Goodman LS, Ran TW, et ai, eds. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985:1333. 16. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978;41 :36-51. 17. Evans WE, Christensen ML. Drug interactions with methotrexate. J Rheumatol 1985;12(suppl 12):15-20. 18. Calabresi P, Parks RE Jr. Antiproliferative agents and drugs used for immunosuppression. In: Gilman AG, Goodman LS, Rail TW, et ai, eds. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985: 1263-7. 19. Hendel J, NyforsA. Impact of methotrexate therapy on the folate status of psoriatic patients. Clin Exp Dermatol 1985; 10:30-5. 20. Campbell MA, Perrier DG, Dorr RT, et al. Methotrexate: bioavailability and pharmacokinetics. Cancer Treat Rep 1985;69:833-8. 21. Wan SH, Huffman DH, Azarnoff DL, et al. Effect of route of administration and effusions on methotrexate pharmacokinetics. Cancer Res 1974;34:3487-91. 22. Hendel L, Hendel J, Johnsen A, et al. Intestinal function and methotrexate absorption in psoriatic patients. Clin Exp Dermatol 1982;7:491-8. 23. Balis FM, Savitch JL, Bleyer W A. Pharmacokinetics of oral methotrexate in children. Cancer Res 1983;43:2342-5. 24. Craft AW, Rankin A, Aherne W. Methotrexate absorption in children with acute lymphoblastic leukemia. Cancer Treat Rep 1981 ;65(suppl I) :77-81. 25. Steele WH, Stuart JFB, Lawrence JR, et al. Enhancement of methotrexate absorption by subdivision of dose. Cancer Chemother Pharmacol 1979;3:235-7. 26. Freeman-Narrod M, Gerstley BJ, Engstrom PF, et al. Comparison of serum concentrations of methotrexate after various routes of administration. Cancer 1975;36:1619-24. 27. WangYM,SutowWW,RomsdahIMM,etaI.Age-related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma. Cancer Treat Rep 1979;63:405-10. 28. Bertino JR. Clinical pharmacology of methotrexate. Med Pediatr OncoI1982;1O:40l-11. 29. Jacobs SA, Bleyer WA, Chabner BA, et al. Altered plasma pharmacokinetics of methotrexate administered intrathecally. Lancet 1975;1:465-6. 30. Tattersall MHN, Parker LM, Pitman SW, et al. Clinical pharmacology ofhigh-dose methotrexate (NSC-740). Cancer Chemother Rep (Part 3) 1975;6:25-9. 31. Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculo-cisternal perfusion. J Pharmacol Exp Ther 1975;195:73-83. 32. Rubin R, Owens E, Rail D. Transport of methotrexate by the choroid plexus. Cancer Res) 968;28:689-94. 33. Hendel J, Nyfors A. Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol 1984;26:121-4. 34. Lawrence JR, Steele WH, Stuart JFB, et al. Dose-dependent methotrexate elimination following bolus intravenous injection. Eur J Clin Pharmacol 1980;17:371-4. 35. Hansen HH, Selawry OS, Holland JF, et al. The variability of individual tolerance to methotrexate in cancer patients. Br J Cancer 1971;25:298-305. 36. Thyss A, Milano G, Kubar J, et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet 1986;1 :256-8. 37. Singh RR, Malaviya AN, Pandey IN, et al. Fatal interaction between methotrexate and naproxen [Letter]. Lancet 1986;):1390.

Volume 25 Number 2, Part I August 1991 38. Maiahe AG. Acute renal failure due to concomitant action of methotrexate and indomethacin [Letter]. Lancet 1986;1:1390. 39. Daly HM, Scott GL, Boyle J, et al. Methotrexate toxicity precipitated by azapropazone. Br J Dermatol 1986;114: 733·5. 40. Jacobs SA, Stoller RG, Chabner BA, et al. 7·Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high-dose methotrexate. 1 Clin Invest 1976;57:534·8. 41. Bender RA. Membrane transport of methotrexate (NSC740) in human neoplastic cells. Cancer Chemother Rep (Part 3) 1975;6:73·82. 42. Hryniuk WM, Bertino lR. Treatment of leukemia with large doses of methotrexate and folinic acid: clinicalbiochemical correlates. J Clin Invest 1969;48:2140-55. 43. Weinstein GD. Methotrexate. Ann Intern Med 1977;86: 199-204. 44. Gelfant S. The cell cycle in psoriasis: a reappraisal. Br J DermatoI1976;95:577-90. 45. Frei E III, Jaffe N, Tattersall MHN, et al. New approaches to cancer chemotherapy with methotrexate. Seminars in Medicine of the Beth Israel Hospital, Boston. Bleich HL, Boro ES, eds. N Engl J Med 1975;292:846-51. 46. Goldie JH, Price LA, Harrap KR. Methotrexate toxicity: correlation with duration of administration, plasma levels, dose and excretion pattern. Eur J Cancer 1972;8:40914. 47. Young RC, Chabner BA. An in vivo method for determining differential effects of chemotherapy on target tissues in animals and man: correlation with plasma pharmacokinetics [Abstract). 1 CIin Invest 1973;52:92a. 48. Levitt M, Mosher MS, Deconti RC. Improved therapeutic index of methotrexate "leucovorin rescue." Cancer Res 1975;59:811·7. 49. IsacoffWH, Townsend CM lr, Eliber FR, eta!' High-dose methotrexate therapy of solid tumors: observations relating to clinical toxicity. Med Pediatr OncoI1976;2:319-25. 50. Roenigk HH lr, Auerbach R, Maibach HI, et al. Methotrexate in psoriasis: revised guidelines. 1 AM ACAD DERMATOL 1988;19:145·56. 51. Pitman SW, Parker LM, Tattersall MHN, et al. Clinical trial of high-dose methotrexate (NSC·740) with citrovorum factor (NSC-3590)-toxicologic and therapeutic observations. Cancer Chemother Rep (Part 3) 1975;6: 43-9. 52. McDonald CJ, Bertino lR. Parenteral methotrexate in psoriasis: a report on the efficacy and toxicity oflong-term intermittent treatment. Arch Dermatol 1969;100:655-68. 53. StollerRG,KaplanHG,CummingsFl,etaI.Aclinicaland pharmacological study of high·dose methotrexate with minimal leucovorin rescue. Cancer Res 1979;39:908-12. 54. Roenigk HH lr, FOWler-Bergfeld W, Curtis GH. Methotrexate for psoriasis in weekly oral doses. Arch Dermatol 1969;99:86-93. 55. Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacyoflowdose methotrexate in rheumatoid arthritis. N Engl 1 Med 1985;312:818-22. 56. Zachariae H, Kragballe K, Sogaard H. Methotrexateinduced liver cirrhosis: studies including serial liver biopsies during continued treatment. Br J DermatoI1980;102:40712. 57. Lewis lH, Schiff E. ACG Committee on FDA-Related Matters. Methotrexate-induced chronic liver injury: guide· lines for detection and prevention. Am J Gastroenterol 1988;88:1337-45. 58. Podurgiel Bl, McGill DB, Ludwig J, et al. Liver injury as-

Pharmacology of methotrexate 317

59. 60. 61. 62. 63. 64.

65. 66. 67.

68. 69. 70. 71. 72,

73. 74. 75. 76. 77.

78. 79. 80. 81.

sociated with methotrexate therapy for psoriasis. Mayo Clin Proc 1973;48:787-92. Mackenzie H. Liver biopsy findings after methotrexate therapy for rheumatoid arthritis (RA) [Abstract]. Clin Pharmacal Ther 1975;17:239. Weinblatt ME, Kremer 1M. Methotrexate in rheumatoid arthritis [Editorial). 1 AM ACAD DERMATOL 1988;19: 126-8. Weinstein G, Roenigk H, Maibach H, et a!' PsoriaSIs-liver-methotrexate interactions: cooperative study. Arch Dermatol 1973;108:36-42. Tolman KG, Clegg DO, Lee RG, et at. Methotrexate and the liver. J RheumatoI1985;12(suppI12):29-34. O'Connor GT, Olmstead EM, Zug K, et al. Detection of hepatotoxicity associated with methotrexate therapy for psoriasis. Arch DermatoI1989;125:1209-17. Coulson IH, McKenzie J, Neild VS, et a!' A comparison of liver ultrasound with liver biopsy histology in psoriatics receiving long-term methotrexate therapy. Br J Dermatol 1987;116:491-5. Perrault 1, McGill DB, Ott Bl, et al. Liver biopsy: complications in 1000 patients and outpatients. Gastroenterology 1978;74:103-6. Piccinino F, Sagnelli E, Pasquale G, et al. Complications following percutaneous liver biopsy: a multicentre retrospective study on 68,276 biopsies. J HepatoI1986;2: 165-73. Robinson JK, Baughman RD, Auerbach R, et al. Meth· otrexate hepatotoxicity in cirrhosis. Consideration of liver biopsies at regular intervals. Arch Dermatol 1980;116: 413-5. Wheeland RG, Burgdorf WHC, Humphrey GB. The flag sign of chemotherapy. Cancer 1983;51:1356-8. Doyle LA, Berg C, Bottino G, et a1. Erythema and desquamation after high-dose methotrexate. Ann Intern Med 1983;98:611-2. Lanzkowsky P, layabose S, Shende At et al. Vasculitis as a complication of high-dose methotrexate in the treatment of acute leukemia [Letter). Am J Dis Child 1976;130:675. Baker H. Intermittent high·dose oral methotrexate therapy in psoriasis. Br 1 Dermatol 1970;82:65-9. Kaplan DL, Olsen EA. Erosion of psoriatic plaques after chronic methotrexate administration. Int J Dermatol 1988;27: 59-62. Lawrenz-Wolf B, Wehinger H. Zur Reaktivierung von Sonnenbranden durch Methotrexat. Klin Padiatr 1988; 200:335-8. Levantine At Almeyda 1. Cutaneous reactions to cytostatic agents. Br J DermatoI1974;90:239-42. Moller H. Cytostatic drugs and inflammation. Lancet 1970;2:427. Goldberg NH, Romola JL, Austin EH, et al. Anaphylactoid type reactions in two patients receiving high dose intravenous methotrexate. Cancer 1978;41 :52-5. Abelson HT, Fosburg MT, Beardsley GP, et al. Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine. J Clin Oneol 1983;1:208·16. Zachariae H, Hansen HE, Sogaard H, et al. Kidney biopsies in methotrexate-treated psoriatics. Dermatologic 1990;181:273-6, . Sostman HD, Matthay RA, Putman CE, et a!. Methotrex· ate-induced pneumonitis. Medicine 1976;55:371-88. LascariAD,StranoAJ,lohnson WW, etal. Methotr~xate­ induced sudden fatal pulmonary reaction. Cancer 1977; 40:1393-7. Gutin PH, Green MR, Bleyer W A, et a1. Methotrexate pneumonitis induced by intrathecal methotrexate therapy:

Journal of the American Academy of Dermatology

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82. 83. 84. 85. 86.

87. 88.

a case report with pharmacokinetic data. Cancer 1976;38: 1529-34. Weiss HD, Walker MD, Wiernik PH. Neurotoxicity of commonly used antineoplastic agents (first oftwo parts). N Engl J Med 1974;291:75-81. Bleyer W A. Current status ofintrathecal chemotherapy for human meningeal neoplasms. Natl Cancer Inst Monogr 1977;46:171-8. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Moo 1975;293:161-6. Doroshow JH, Locker GY, Gaasterland DE, et al. Ocular irritation from high-dose methotrexate therapy: pharmacokinetics ofdrug in the tear film. Cancer 1981;48:2158-62. Shamberger RC, Rosenberg SA, Seipp CA, et a!. Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma. Cancer Treat Rep 1981;65:739-46. Tugwell P, Bennett K, Gent M, et aJ. Methotrexate in rheumatoid arthritis. Ann Intern Med 1987;107:418-9. Bailin PL, Tindall JP, Roenigk HH Jr, et aJ. Is methotrex-

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ABSTRACTS Pretibial epidermolysis buIlosa Valcuende Cavero F, Massmanian A, Aniz Montes E, et al. Aetas Derma-Sif 1990;81 :42-5 (Spanish) The authors studied a patient with pretibial epidermolysis bullosa. lmmunohistochemical study of the lesions showed that the bullous pemphigoid antigen, type IV collagen, and laminin formed the roof of the blister. Electron microscopy demonstrated that dermocpidermal separation occurred beneath the lamina densa. Adecrease in anchoring fibils was also observed. The authors conclude that pretibial epidermolysis bullosa is a specifie clinical form ofdystrophic epidermolysis bullosa with a dominant autosomal transmission. Yehudi M. Felman, MD

Ichthyosis and steroid sulfatase: Study of enzymatic activity in leukocytes and fibroblasts-variations with sex and type of ichthyosis Piraud M, Cambazard F, Barrut D. Pediatrie 1990;45:133-40 (French) Steroid sulfatase and arylsulfatase C were determined in fibroblasts and/or laukocytes of patients with different types of ichthyosis. Of the 21 patients studied, II showed clinical characteristics of X-linked ichthyosis and a deficiency of these two enzymatic activities. Patients affected with other types of ichthyosis showed no enzymatic deficiency. Yehudi M. FelmC/Il, M D