      Document 0210
 DOCN  DRG0210
 UNIQUE IDENTIFIER        DRG-0037
 NAME OF SUBSTANCE        Piritrexim isethionate [USAN 1995]
 REGISTRY NUMBER          79483-69-5
 RELATED REGISTRY NUMBER  72732-56-0
 STANDARD CHEMICAL NAME   Pyrido(2,3-d)pyrimidine-2,4-diamine,
                          6-((2,5-dimethoxy-phenyl)methyl)-5-methyl-,
                          mono(2-hydroxyethanesulfonate) [USAN 1996]
 SYNONYMS                 2,4-Diamino-6-(2,5-dimethoxybenzyl)-5-
                          methylpyrido(2,3-d)pyrimidine mono-(2
                          hydroxyethanesulfonate) [USAN 1995]
 PROTOCOL ID NUMBERS      NIAID 89 CC-59
 SECONDARY SOURCE ID      BW 301U (isethionate) [USAN 1995]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: A lipid-soluble dihydrofolate
                          reductase (DHFR) inhibitor with the same
                          mechanism of action as Trimethoprim against
                          Pneumocystis carinii. [Antimicrob Agents
                          Chemother 1988;32:430-3] Inhibits the
                          activity of Pneumocystis carinii DHFR enzyme
                          in vitro at levels from 140-2000 fold less
                          than that required by Trimethoprim and
                          Pyrimethamine for similar inhibition. The
                          basis for the anti-folate activity of
                          Piritrexim is its inhibition of DHFR, an
                          essential folate conversion enzyme for
                          protozoan and mammalian cells. Its
                          lipid-soluble nature enables it to diffuse
                          across the protozoan membrane without the use
                          of a transport mechanism (the resultant
                          myelosuppressive effect following passive
                          diffusion in mammalian cells can be
                          counteracted by use of Leucovorin (folinic
                          acid)). Similar to Trimetrexate in terms of
                          activity, pharmakinetics and safety in cancer
                          patients. Following oral dosing in cancer
                          patients, Piritrexim peak serum levels were
                          obtained in 1.6 hours, with a half-life of
                          4-5 hours. In patients receiving Piritrexim
                          orally once daily for 5 consecutive days, the
                          principal pharmacokinetic parameters
                          indicated a plasma half-life of 3-4 hours, a
                          time to maximum serum concentration of
                          2.0-2.5 hours, and a maximum concentration of
                          approximately 5 micrograms/ml for doses of
                          approximately 480 mg/sq-m. Oral
                          bioavailability of Piritrexim is about 65
                          percent, and it is 92-95 percent bound to
                          plasma protein. [NIAID 89 CC-59]
 DISEASES STUDIED/TREATED Pneumocystis carinii pneumonia (PCP) [USP DI
                          1995]
 CLASSIFICATION CODE      Antifolate (piritrexim) [AmFAR Tx Dir 1993
                          April;6(3)]
 CLASSIFICATION CODE      Antineoplastic (piritrexim) [AmFAR Tx Dir
                          1993 April;6(3)]
 CLASSIFICATION CODE      Antiprotozoal (piritrexim) [AmFAR Tx Dir 1993
                          April;6(3)]
 CLASSIFICATION CODE      Antiproliferative [USAN 1995]
 OTHER MAJOR USES         Used as an anti-cancer agent [USP DI 1995]
 SUBSTANCE INTERACTIONS   Administer with leucovorin to prevent
                          piritrexim myelosuppression. [USP DI 1995]
 ADVERSE EFFECTS          Leukopenia, anemia, thrombocytopenia, nausea
                          and vomiting, mucositis and myelosuppression
                          are the main adverse reactions. [USP DI 1995]
 CONTRAINDICATIONS        Should not be used by patients who have had a
                          history of adverse reaction to Trimetrexate
                          requiring discontinuation of treatment, or by
                          pregnant or lactating women, or by women or
                          men not practicing birth control. [NIAID 89
                          CC-59]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Methotrexate analog. [USP
                          DI 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION:  Off-white, odorless
                          powder [NIAID 89 CC-59]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C17H19N5O2.C2H6O4S [USAN
                          1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT:  451.50 [USAN 1995]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Lipid soluble. [USP DI 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM:  Tablets (25 mg). [NIAID 89
                          CC-59]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY:  Oral, intravenous [USP DI
                          1995]
 SUBSTANCE DELIVERY DATA  STORAGE:  Store at 15-30 C (59-86 F). [NIAID
                          89 CC-59]
 MANUFACTURERS            Glaxo Wellcome
 REFERENCES               Perkins W, Williams RE, Vestey JP, Tidman MJ,
                          Layton AM, Cunliffe WJ, Saihan EM, Klaber MR,
                          Manna VK, Baker H, et al. A multicentre
                          12-week open study of a lipid-soluble folate
                          antagonist, piritrexim in severe psoriasis.
                          Br J Dermatol 1993 Nov;129(5):584-9.
 REFERENCES               de Wit R, Verweij J, Slingerland R, Stoter G.
                          Piritrexim-induced pulmonary toxicity. Am J
                          Clin Oncol. 1993 Apr;16(2):146-8.
 REFERENCES               Sattler FR, Feinberg J. New developments in
                          the treatment of Pneumocystis carinii
                          pneumonia. Chest 1992 Feb;101(2):451-7.
 REFERENCES               Adamson PC, Balis FM, Miser J, Arndt C, Wells
                          RJ, Gillespie A, Aronson L, Penta JS,
                          Clendeninn NJ, Poplack DG. Pediatric phase I
                          trial, pharmacokinetic study, and limited
                          sampling strategy for piritrexim administered
                          on a low-dose, intermittent schedule. Cancer
                          Res. 1992 Feb 1;52(3):521-4.
 REFERENCES               Hughes WT. Prevention and treatment of
                          Pneumocystis carinii pneumonia. Annu Rev Med.
                          1991;42:287-95.
 REFERENCES               Guzzo C, Benik K, Lazarus G, Johnson J,
                          Weinstein G. Treatment of psoriasis with
                          piritrexim, a lipid-soluble folate
                          antagonist. Arch Dermatol. 1991
                          Apr;127(4):511-4.
 REFERENCES               Falloon J, Kovacs J, Allegra C, O'Neill D,
                          Tuazon C, Frame P, Dohn M, Joseph P,
                          Feuerstein I, LaFon S, et al. A pilot study
                          of piritrexim (PTX) with leucovorin (LCV) for
                          the treatment of pneumocystis pneumonia. Int
                          Conf AIDS. 1990 Jun 20-23;6(1):221 (abstract
                          no. Th.B.399).
 ENTRY MONTH              8909
 LAST REVISION DATE       960612
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
