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At least 19 recordsLinked to original sources
PubMed2005

Adsorption of 6-mercaptopurine and 6-mercaptopurine-ribosideon silver colloid: a pH-dependent surface-enhanced Raman spectroscopy and density functional theory study. II. 6-mercaptopurine-riboside.

Surface-enhanced Raman spectroscopy (SERS) has been applied to characterize the interaction of 6-mercaptopurine-ribose (6MPR), an active drug used in chemotherapy of acute lymphoblastic leukemia, with a model biological substrate at therapeutic concentrations and as function of the pH value. Therefore, a detailed vibrational analysis of crystalline and solvated (6MPR) based on Density Functional Theory (DFT) calculations of the thion and thiol tautomers has been performed. 6MPR adopts the thion tautomeric form in the polycrystalline state. The SERS spectra of 6MPR and 6-mercaptopurine (6MP) recorded on silver colloid provided evidence that the ribose derivative shows different adsorption behavior compared with the free base. Under acidic conditions, the adsorption of 6MPR on the metal surface via the N7 and possibly S atoms was proposed to have a perpendicular orientation, while 6MP is probably adsorbed through the N9 and N3 atoms. Under basic conditions both molecules are adsorbed through the N1 and possibly S atoms, but 6MP has a more tilted orientation on the silver colloidal surface while 6MPR adopts a perpendicular orientation. The reorientation of the 6MPR molecule on the surface starts at pH 8 while in the case of 6MP the reorientation starts around pH 6. Under basic conditions, the presence of the anionic molecular species for both molecules is suggested. The deprotonation of 6MP is completed at pH 8 while the deprotonation of the riboside is finished at pH 10. For low drug concentrations under neutral conditions and for pH values 8 and 9, 6MPR interacts with the substrate through both N7 and N1 atoms, possibly forming two differently adsorbed species, while for 6MP only one species adsorbed via N1 was evidenced.

Adsorption↗
PubMed1995

The absorption of 6-mercaptopurine from 6-mercaptopurine riboside in rat small intestine: effect of phosphate.

The intestinal absorption of 6-mercaptopurine and its nucleoside 6-mercaptopurine riboside has been studied in the rat with the in situ dual luminal and vascular perfusion. 6-Mercaptopurine is an inactive prodrug that requires intestinal absorption, cellular uptake and intracellular anabolism for cytotoxic activity. Vascular and mucosal samples were analysed by high-performance liquid chromatography (HPLC) to assess the rate of vascular appearance and amounts of thiopurine and its nucleoside in the mucosa. With 5 mmol luminal 6-mercaptopurine/l, the drug is transported across the intestine unchanged at a rate of 0.053 +/- 0.006 mumol min-1 (g dry wt.)-1. At concentrations below 20 mmol/l, 6-mercaptopurine riboside is not transported across the intestine intact but is split by phosphorolysis in the intestinal mucosa. The rate of vascular appearance of 6-mercaptopurine [0.043 +/- 0.005 mumol min-1 (g dry wt.)-1] from 5 mmol luminal 6-mercaptopurine riboside/l did not differ significantly from that seen with 5 mmol luminal 6-mercaptopurine/l. When the lumen was perfused with 6-mercaptopurine riboside the riboside appeared in the tissue together with a higher mucosal concentration of 6-mercaptopurine than in perfusions with 6-mercaptopurine. Some metabolism of 6-mercaptopurine to 6-thioguanine was also observed; however, no 6-thioguanine appeared in the vascular effluent. Increasing the luminal phosphate concentration from 2 to 10 mmol/l increased mucosal phosphorolysis of 6-mercaptopurine riboside and more than tripled the rate of vascular appearance of 6-mercaptopurine; conversion of 6-mercaptopurine to 6-thioguanine was significantly inhibited. These results suggest that with a modest increase in luminal phosphate concentration, 6-mercaptopurine riboside can be a more effective substrate than the free drug for the oral delivery of 6-mercaptopurine.

Animals↗
PubMed1985

The effects of 6-mercaptopurine nucleotide derivatives on the growth and survival of 6-mercaptopurine-sensitive and -resistant cell culture lines.

6-Mercaptopurine (MP)-sensitive and -resistant cell culture lines were used to further characterize the apparent ability of MP nucleotide derivatives to overcome resistance to the parent drug. 6-Mercaptopurine-9-beta-D-ribofuranoside 5'-monophosphate [MPRP], bis(6-mercaptopurine-9-beta-D-ribofuranoside)-5', 5"'-monophosphate [bis(MPR)P], bis(O2',O3'-dibutyryl-6-mercaptopurine-9-beta-D-ribofuranoside)-5', 5"'-monophosphate [bis(dibut.MPR)P], and O2',O3'-dibutyryl-6-mercaptopurine-9-beta-D-ribofuranoside 5'-monophosphate [dibut.MPRP] were tested for cytotoxic and/or growth inhibitory effects against MP-resistant sublines of V79 Chinese hamster lung fibroblasts (CH/TG) and L1210 mouse leukaemia cells (L1210/MPR) in which deficiencies of hypoxanthine-guanine phosphoribosyltransferase, and hence drug nucleotide forming capacity were the basis of resistance. L1210/MPR cells were totally resistant to 1 mM 6-mercaptopurine-9-beta-D-ribofuranoside [MPR] and 2 mM MPRP, but were inhibited by high concentrations (greater than 0.25 mM) of bis(MPR)P. These results suggested that bis(MPR)P was taken up by cells as the intact molecule since MPR and MPRP were its extracellular breakdown products. L1210/MPR cells were much more sensitive to the lipophilic bis(dibut.MPR)P derivative which had a predominantly cytotoxic action as judged by trypan blue staining and the ability of treated cells to produce macroscopic colonies in soft agar medium. However, cells killed by bis(dibut.MPR)P did not disintegrate appreciably over periods of up to 10 days. The effects of bis(dibut.MPR)P were probably the result of cellular uptake of the intact molecule. Dibut.MPRP showed minimal ability to inhibit L1210/MPR cells although this compound was a possible breakdown product of bis(dibut.MPR)P and a source of the same extracellular degradation products. The median cell size decreased in L1210/MPR cultures during exposure to both bis(MPR)P and bis(dibut.MPR)P. This effect was elicited more rapidly and at lower concentration by bis(dibut.MPR)P than by bis(MPR)P. In contrast, sodium butyrate, a breakdown product of bis(dibut.MPR)P induced increases in cell size at high concentration. Bis (dibut.MPR)P was also cytotoxic to MP-resistant CH/TG cells and was approximately 300 times more effective than bis(MRP)P and MPR which exhibited similar activity against this cell line. Bis(dibut.MPR)P and dibut.MPRP were equivalent and less active than MPR in their effects on MP-sensitive L1210/0 cells where their predominant mechanism of action was via degradation to release MPR.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: bisacyloxymethyl-6-mercaptopurine prodrugs.

A series of S6,9-bisacyloxymethyl-6-mercaptopurine (6,9-bis-6-MP) prodrug derivatives was synthesized and characterized. The solubilities of the derivatives in solvents (vehicles), which exhibited a wide range of polarities from water to oleic acid, were measured. The abilities of the prodrugs to deliver 6-mercaptopurine (6-MP) from the vehicles have also been determined, and experimental fluxes and permeability coefficients (Kp) have been calculated for a large number of prodrug: vehicle combinations. Generally the best prodrugs of the series in terms of delivering 6-MP, regardless of the vehicle, were the first two members--the bisacetyl- and the bispropionyloxymethyl-6-mercaptopurine prodrugs. This result has been attributed mainly to the increased water solubility of these two prodrugs compared with that of 6-MP and the other prodrugs, since all of the prodrugs are much more lipid soluble than 6-MP. For three vehicles--isopropyl myristate, propylene glycol, and water--there was a good correlation between log experimental Kp for the delivery of 6-MP by the prodrugs from those vehicles and the theoretical solubility parameters of the prodrugs. The stabilities of the bisacetyl-(2), bisproprionyl-(3), and bisbutyryloxymethyl-6-mercaptopurine (4) derivatives were determined in buffer and in buffer containing enzymes leached from the dermis. Prodrug 2 was more stable than 3 or 4 in the buffer containing the enzymes, while 4 was more stable than 2 or 3 in the plain buffer.

Animals↗
PubMed1980

Comparison of prednisolone, vincristine, methotrexate and 6-mercaptopurine vs. 6-mercaptopurine and prednisone maintenance therapy in childhood acute leukemia: a Southwest Oncology Group Study.

The study was designed to compare the relapse rate and toxicity of intermittent prednisone, oncovin (vincristine), methotrexate, and 6-mercaptopurine (POMP) vs. 6-mercaptopurine daily and a prednisone pulse every three months (PIP) for maintenance therapy in acute leukemia. Children with acute lymphoblastic, acute undifferentiated, or acute stem-cell leukemia were stratified on the basis of initial leukocyte count and age, then randomly assigned to POMP or PIP maintenance therapy. All patients received cranial irradiation and intrathecal chemotherapy. Of the 67 patients receiving POMP maintenance, 20(30%) remain in continuous remission. The median length of continuous remission achieved with POMP therapy was 49 weeks. Of 80 patients receiving PIP maintenance, 25(31%) remain in remission. The median length of continuous remission for PIP was 62 weeks. Of the possible prognostic factors evaluated, the only significant factor was the prognostic grouping base in age and initial leukocyte regimen was associated with a higher incidence of toxic reactions, frequently causing therapy interruption. The results for both regimens as studied are inferior to those for 6-mercaptopurine methotrexate maintenance regimens as reported by others.

Age Factors↗
PubMed1988

Effects of vehicles and prodrug properties and their interactions on the delivery of 6-mercaptopurine through skin: S6-acyloxymethyl-6-mercaptopurine prodrugs.

A homologous series of S6-acyloxymethyl-6-mercaptopurine (6-mono-6-MP) and two 9-acyloxymethyl-6-mercaptopurine (9-mono-6-MP) prodrugs have been synthesized and characterized. The ability of the 6-mono-6-MP prodrugs to deliver 6-mercaptopurine (6-MP) through hairless mouse skin from isopropyl myristate (IPM) and propylene glycol (PG) has been evaluated. There was a good correlation between the log experimental permeability coefficients from the diffusion data and calculated solubility parameters of the prodrugs. Although there was no statistical difference between the rates of delivery of 6-MP by the acetyl through valeryl 6-mono-6-MP prodrugs from IPM, the butyryl and valeryl prodrugs were significantly better at delivering 6-MP from PG. For a given solubility parameter value, the 6-mono-6-MP prodrugs were less soluble in water and IPM, and more soluble in PG than the previously studied S6,9-bisacyloxymethyl-6-MP (6,9-bis-6-MP) prodrugs. On the other hand, for a given solubility parameter, the 6,9-bis-6-MP prodrugs were generally more effective at delivering 6-MP from IPM and PG. The single 9-mono-6-MP prodrug that was evaluated was much less effective at delivering 6-MP than either the 6-mono- or 6,9-bis-6-MP prodrugs. Thus, it is much less important to mask the imidazole than the thionamide functional group in 6-MP to enhance the topical delivery of 6-MP using a prodrug approach.

Animals↗
PubMed1982

A Purinethol (6-mercaptopurine) fatality in a case of prescription negligence: a gas chromatographic determination of 6-mercaptopurine.

A 64-year-old white female was given Purinethol (6-mercaptopurine) in place of propylthiouracil. A gas chromatographic method for the determination of 6-mercaptopurine in blood and other biological tissues has been developed. Samples were extracted with chloroform/isopropanol (4:1) at pH 7.0 and back-extracted into 0.5N sodium hydroxide (NaOH). The NaOH fraction was neutralized and buffered at pH 7.0 and extracted with chloroform/isopropanol (4:1). Quantitation was made by gas chromatography following methylation of the drug with trimethylanilinum hydroxide on an OV-101 or OV-225 column, using an internal standard. 6-Mercaptopurine was identified in all tissues by gas chromatography/mass spectrometry. The derivatized drug was identified by its electron impact mass spectrum as a dimethylated compound that has a molecular ion at m/e 180, which is also the base peak. The highest concentration of Purinethol was found in blood (110 mg/L). Concentrations in other tissues have been given. This is probably the first reported death by Purinethol.

Chemical and Drug Induced Liver Injury↗
PubMed1990

Effect of aminomethyl (N-Mannich base) derivatization on the ability of S6-acetyloxymethyl-6-mercaptopurine prodrug to deliver 6-mercaptopurine through hairless mouse skin.

A series of 9-aminomethyl-S6-acetyloxymethyl-6-mercaptopurine (9-AM-6-AOM-6-MP) prodrugs have been synthesized and characterized, and their ability to deliver total 6-mercaptopurine (6-MP) through hairless mouse skin has been measured. The 9-AM-6-AOM-6-MP prodrugs are much more soluble in isopropyl myristate (IPM) than S6-acetyloxymethyl-6-MP (6-AOM-6-MP) itself or the corresponding 7-aminomethyl-6-MP (7-AM-6-MP) prodrugs. The 9-AM-6-AOM-6-MP prodrugs were all more effective (1.8-4 times) than 6-AOM-6-MP at delivering total 6-MP, except for the piperidylmethyl derivative which only gave a comparable rate of delivery. The 9-AM-6-AOM-6-MP prodrugs were also more effective (7-27 times) than the corresponding 7-AM-6-MP prodrugs at delivering 6-MP, except for the diethylaminomethyl derivative which only gave a comparable rate of delivery. In contrast to the 9-aminomethyl-S6-pivaloyloxymethyl-6-MP (9-AM-6-POM-6-MP) derivatives which generally delivered as much or more intact S6-pivaloyloxymethyl-6-MP (6-POM-6-MP) as 6-MP, the 9-AM-6-AOM-6-MP derivatives delivered mainly (80-95%) 6-MP from IPM. There was a direct correlation between log experimental permeability coefficients for delivery of total 6-MP (P sigma) and the calculated solubility parameter values for the 9-AM-6-AOM-6-MP prodrugs(delta j), with the P sigma generally decreasing as the value of delta j approached that of the vehicle, IPM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

The quantitative determination of metabolites of 6-mercaptopurine in biological materials. VI. Evidence for posttranscriptional modification of 6-thioguanosine residues in RNA from L5178Y cells treated with 6-mercaptopurine.

Mammalian cells incorporate 6-thioguanosine into their nucleic acids when grown in the presence of 6-mercaptopurine. 35S-labeled total RNA was prepared from L5178Y murine lymphoma cells grown in vitro in the presence of 6-[35S]mercaptopurine. Base analyses of this RNA suggested that 6-thioguanosine residues in RNA molecules undergo posttranscriptional modification. Thus, enzymatic peak-shifting analyses using anion-exchange high-performance liquid chromatography were applied to the hydrolysis products released from total RNA preparations by digestion with nuclease P1 or nuclease P1 plus nucleotide pyrophosphatase. At least eight 35S-labeled, phosphatase-sensitive compounds structurally different from [35S]6thioGMP were found in nuclease P1 digests. Four of these compounds were susceptible to cleavage with nucleotide pyrophosphatase, thus indicating that they contained phosphoric acid anhydride bonds. Individual RNA species were not separately examined, the radiochromatographic data, however, which were obtained from digests of total RNA preparations, present evidence that 6-thioguanosine 5'-diphosphate and 6-thioguanosine 5'-triphosphate exist as 5'-terminal starting nucleotides (in tRNA and rRNA) and that 6-thioguanosine becomes incorporated into the highly modified dinucleoside triphosphate structures (caps) which commonly block the 5'-termini of eukaryotic poly(A)+ mRNA-molecules.

Animals↗
PubMed2001

Comparative pharmacokinetics of oral 6-mercaptopurine and intravenous 6-mercaptopurine riboside in children.

BACKGROUND: The poor absorption of orally administered 6-mercaptopurine (6MP) causes a wide variation in its cytotoxic efficacy. An i.v. dosage form would eliminate this problem. Our objective was to compare the pharmacokinetics of 6MP administered orally with those of an i.v. dosage form 6-mercaptopurine riboside (6MPR), in children with acute lymphoblastic leukemia or malignant lymphoma. METHODS: A total of 10 children were treated with oral 6MP, 50 mg/m(2) per day, while five children were treated with 6MPR, 50 mg/m(2) per day, administered by rapid i.v. injection. The plasma concentrations of 6MP and of 6MPR were measured on day 0, while the concentrations of 6-thioguanine nucleotides (6TGN) in red blood cells (RBC) were measured on day 2. The area under the plasma concentration-time curve (AUC1-5) was calculated from 1 to 5 h after drug administration. RESULTS: With the intravenously administered 6MPR, the AUC1-5 ranged from 124 to 186 (1.5-fold range, median 145) microM min; only two samples were obtained for the RBC concentration of 6TGN, and were 121 and 273 pmol per 25 mg hemoglobin. With the orally administered 6MP, the AUC1-5 ranged from 23 to 65 microM min (2.8-fold range, median 56); the RBC concentration of 6TGN ranged from 18 to 152 pmol per 25 mg hemoglobin (median 75). CONCLUSION: The i.v. administration of 6MPR showed less interindividual variation in the AUC1-5 coupled with a higher RBC level of 6TGN as compared with those by oral 6MP. We conclude that the i.v. administration of 6MPR achieves stable blood levels of active drug in children undergoing cancer chemotherapy.

Administration, Oral↗
PubMed2000

A mixed-valence iron complex of the antitumour drug 6-mercaptopurine: tris(6-mercaptopurine)iron(II) tetrachloroferrate(III) chloride.

Single crystals of the title complex, tris(1, 6-dihydro-9H-purine-6-thione-N(7),S)iron(II) tetrachloroferrate(III) chloride, [Fe(C(5)H(4)N(4)S)(3)][FeCl(4)]Cl, were grown on the surface of solid 6-mercaptopurine monohydrate pellets in a solution of iron(III) chloride. The solution of the hexagonal structure required the application of twin refinement techniques. All the component ions lie on threefold rotation axes. The complex contains distorted octahedral [Fe(C(5)H(4)N(4)S)(3)](2+) cations with three N7/S6-chelating neutral 6-mercaptopurine ligands, tetrahedral [FeCl(4)](-) anions with a mean Fe-Cl distance of 2.189 (1) A, and free chloride ions.

Antineoplastic Agents↗
PubMed1990

[Mercaptopurine and silylated mercaptopurine the treatment of experimental allergic encephalomyelitis].

The therapeutic effects of mercaptopurine (6-mercaptopurine, 6-MP) and a silylated derivative (6-trimethylsilylthio-9-trimethyl-silylpurine, S-MP) were compared on the course of T lymphocyte line mediated experimental allergic encephalomyelitis (t-EAE). This transferred EAE is a passively induced model disease in Lewis rats easy to elicit, reliably reproducible and characterized by a dose-dependent lethality. If given at different points in single injections the silicon derivative is shown to be more efficient than 6-MP (43/125 surviving animals compared to 26/129), severity of disease is attenuated and number of survivors increased. Silylation is able to improve blood-brain barrier and cellular permeability; S-MP suppresses intrathecal inflammatory cells more effectively than the original immunosuppressant.

Animals↗
PubMed1998

Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial.

PURPOSE: To determine whether early intensification with 12 courses of intravenous methotrexate and intravenous mercaptopurine (IVMTX/IVMP) is superior to 12 courses of repetitive, low-dose oral MTX with I.V. MP (LDMTX/IVMP) for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Seven hundred nine patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction. Patients were randomized to receive intensification with either IVMTX 1,000 mg/m2 plus IVMP 1,000 mg/m2 (regimen A) or LDMTX 30 mg/m2 every 6 hours for six doses with IVMP 1,000 mg/m2 (regimen B). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy (TIT) was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and TIT every 12 weeks for 2 years. RESULTS: Six hundred ninety-nine (99%) patients achieved remission. Three hundred forty-nine were assigned to regimen A and 350 to regimen B. The estimated 4-year continuous complete remission (CCR) rate for patients treated with regimen A is 80.3% (SE = 2.9%) and with regimen B is 75.9% (SE = 3.1%). By log-rank analysis, regimen A demonstrated superior CCR (P = .013). Transient neutropenia/thrombocytopenia, bacterial sepsis, neurotoxicity, stomatitis, and hospitalizations were more frequent among patients treated on regimen A. CONCLUSION: Intensification with IVMTX/IVMP is more effective than LDMTX/IVMP for prevention of relapse in children with B-precursor ALL at lower risk for relapse.

Administration, Oral↗
PubMed1978

[6-(2,4-Dinitrophenyl)-mercaptopurine, a stronger immunosuppressive drug than 6-mercaptopurine to primary humoral T-cell dependent immune response in mice].

The suppressive effect of 6-(2,4-Dinitrophenyl)-mercatopurine (DNP-MP) and 6-mercaptopurine (MP) was investigated on the early primary immune response of mice against the T-cell dependent antigens DNP49-bovine gamma globuline (BGG), sheep red blood cells (SRBC) or FITC8-BCG and the T-cell independent DNP22-Ficoll. The number of IgM antibody forming cells (AbFC) to the hapten determinants and to the SRBCs per 10(6) spleen cells was determined. DNP-MP reduced the number of AbFCs after the immunisation with the T cell dependent antigens always stronger than the MP, independently of the antigen type by which the mice had been immunised. The Anti-DNP22-Ficoll immune response was suppressed equally by both immunosuppressive drugs. DNP-MP is not a specific immunosuppressive drug for the anti-DNP-B-lymphocytes. Helper T-cells and macrophages are discussed as target cells for the stronger unspecific action of DNP-MP.

Animals↗