Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats

Purpose: To define the plasma concentrations of butyrate achieved and the profile of plasma butyrate concentrations versus time in mice and rats treated with tributyrin or sodium butyrate. Methods: Female CD₂F₁ mice were treated with tributyrin by oral gavage or with sodium butyrate by i.v. bolus or oral gavage. Oral tributyrin doses delivered to mice were 3.1, 5.2, 7.8, and 10.3 g/kg. Intravenous sodium butyrate doses were 0.31, 0.62, 0.94, and 1.25 g/kg. Oral sodium butyrate was given to mice at 5 g/kg. Subsequently, similar studies were performed in female Sprague-Dawley rats. Rats were given tributyrin by oral gavage at doses of 3.6, 5.2, or 10.3 g/kg or sodium butyrate i.v. at a dose of 500 mg/kg. Plasma butyrate concentrations were determined by gas chromatography. Results: In mice, oral dosing with tributyrin resulted in detectable plasma butyrate concentrations as early as at 5 min after treatment and produced peak plasma butyrate concentrations at between 15 and 60 min after dosing. Peak plasma butyrate concentrations increased proportionally with increasing tributyrin dose, but as the oral tributyrin dose increased there was a greater than proportional increase in the area under the curve of plasma butyrate concentrations versus time (AUC). At a tributyrin dose of 10.3 g/kg, plasma butyrate concentrations peaked at approximately 1.75 mM and remained ≥1 mM for between 10 and 60 min after dosing. However, approximately 10% of mice treated with this dose died acutely. At a tributyrin dose of 7.8 g/kg, plasma butyrate concentrations reached approximately 1 mM by 15 min after dosing and remained between 0.8 and 1 mM until 60 min after dosing. No mouse treated with this dose died acutely. Mice given tributyrin doses of 5.2 and 3.1 g/kg achieved peak plasma butyrate concentrations of approximately 0.9 and 0.5 mM, respectively, by 45 min after dosing. Plasma butyrate concentrations in these mice remained above 0.1 mM until 120 and 90 min after dosing, respectively. The four i.v. doses of sodium butyrate resulted in plasma concentration-time profiles that also indicated nonlinear pharmacokinetics and were well described by a one-compartment model with saturable elimination. Values recorded for the Michaelis-Menten constant (K _m) and the maximal velocity of the process (V_max) ranged between 1.02 and 5.65 mM and 0.60 and 1.82 mmol/min, respectively. Values noted for the volume of the central compartment (V_c) varied between 0.48 and 0.72 l/kg. At 1.25 g/kg, i.v. sodium butyrate produced peak plasma butyrate concentrations of 10.5–17.7 mM, and plasma butyrate concentrations remained above 1 mM for 20–30 min. Sodium butyrate delivered orally to mice at 5 g/kg produced peak plasma butyrate concentrations of approximately 9 mM at 15 min after dosing and plasma butyrate concentrations exceeding 1 mM for 90 min after dosing. In rats the 10.3-g/kg oral dose of tributyrin produced peak plasma butyrate concentrations of approximately 3 mM by 75 min after dosing and butyrate concentrations excedding 1 mM from 30 to 90 min after dosing. The plasma butyrate concentrations produced in rats by 5.2- and 3.6-g/kg doses were appropriately lower than those produced by the 10.3-g/kg dose, and there was no evidence of nonlinearity. The 500-mg/kg i.v. dose of sodium butyrate produced peak plasma butyrate concentrations in rats of approximately 11 mM, and the decline in plasma butyrate concentrations with time after dosing was consistent with saturable clearance. Conclusion: These studies document the ability to use oral administration of tributyrin to achieve pharmacologically relevant concentrations of butyrate in rodent plasma. They also document the nonlinear nature of butyrate clearance. These data are being used in the design of clinical trials of oral tributyrin in patients with malignancies and hemoglobinopathies. Received: 27 July 1998 / Accepted: 3 November 1998     

Reversal of 5-fluorouracil-induced toxicity by oral administration of uridine

BACKGROUND:: Previous preclinical and clinical investigations have shownthat the combined administration of 5-fluoro-uracil (5-FU) withdelayed uridine can reverse side effects induced by 5-FU. Thisbiochemical modulation-based combination may increase the therapeuticindex of 5-FU PATIENTS AND METHODS:: Seven patients with advanced cancer were treated weekly with5-FU at increasing dosages starting at a dose of 600 mg/m².Five patients developed dose-limiting leukopenia, and two patientsdeveloped thrombocytopenia. At the dose-limiting toxicity level,5-FU treatment was repeated and followed after 3 hours by oraluridine (5 g/m² q 6 hr) during 72 hours. RESULTS:: 5-FU-induced leukopenia was reversed for several weeks afterthe administration of oral uridine. However, thrombocytopeniawas not reversed. Side effects of the combined treatment consistedof mild diarrhea in five of the seven patients. CONCLUSIONS:: These data indicate that oral uridine can reduce the severityof 5-FU-induced myelosuppression. biochemical modulation, chemotherapy-induced toxicity, 5-fluorouracil, uridine     

Use of oral uridine as a substitute for parenteral uridine rescue of 5-fluorouracil therapy,with and without the uridine phosphorylase inhibitor 5-benzylacyclouridine

Summary Initial clinical trials have demonstrated that uridine (Urd) rescue given i.v. over at least 3 days can ameliorate 5-fluorouracil (FUra) toxicity; to avoid Urd-induced phlebitis in the peripheral veins of patients, a central vein is used. The latter necessity, along with the need for 3 days of i.v. administration, makes Urd rescue by parenteral means a cumbersome and complicated clinical procedure. It would appear preferable to use oral Urd; however, the oral Urd dose in the clinic is limited, as high doses cause diarrhea. Therefore, using a tumor-bearing murine model we investigated as to whether low doses of oral Urd coupled with a Urd phosphorylase inhibitor benzylacyclouridine (BAU), would effect safe rescue of FUra toxicity with preservation of antitumor activity. A high-dose FUra-containing drug combination that included parenteral Urd rescue was used as a control; other groups of tumor-bearing mice received the same drug combination, except that p.o. Urd was substituted for i.p. Urd. In the absence of BAU, p.o. Urd could effect rescue while maintaining an antitumor effect comparable to that obtained with i.p. Urd. When given concomitantly with BAU, a 50% reduction in the oral Urd dose (i.e., from 4,000 to 2,000 mg/kg) enabled the achievement of a comparable therapeutic index. Intraperitoneal Urd produces very high (6–8 mM) plasma and tissue Urd levels, which remain above 100 M for at least 6 h. In contrast, neither oral Urd nor oral BAU alone raised plasma Urd concentrations above about 50 M. However, the combination of oral Urd plus oral BAU gave a peak plasma Urd level of about 300 M, and the level was maintained above 100 M for 6 h. Following oral Urd administration, gut tissue levels of Urd were in the mM range and those of BAU were in the range of 10–20 g/g tissue, a level sufficient to result in substantial inhibition of Urd phosphorylase. Oral Urd plus oral BAU appears to be a promising clinical alternative to parenteral administration of Urd for selective rescue of FUra toxicity.Abbreviations used BAU benzylacyclouridine - FUra 5-fluorouracil - (FUra)RNA RNA containing incorporated FUra - LV leucovorin - MTX methotrexate - PALA N-phosphonacetyl-l-aspartate - Urd uridine Supported in part by Public Health Service grant CA 25842 from the national Cancer Institute, National Institutes of Health, Department of Health and Human Services, and in part by a grant from the Chemotherapy Foundation of New York     

Anosmia or hyposmia after long-term oral administration of tegafur--improved anosmia

Seventeen patients who manifested anosmia or hyposmia after long-oral administration of Tegafur (FT-207) in postoperative chemotherapy for cancer were followed up. Anosmia improved in 9 of 17 patients (52.9%), and the recovery period was between 3 and 42 months after the manifestation, and between 1 and 35 months after discontinuation of FT-207. Rhinoscopy and radiography revealed no abnormal findings in the nasal septum, rima oflactoria, concha nasalis media, sinus ethmoidales, etc. As it took a long time to recover from these signs and symptoms, they were presumed to be due to reversible neurological anosmia or hyposmia.     

Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: implications for uridine rescue regimens in chemotherapy

PURPOSE: The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the oral bioavailability of uridine. PTAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). METHODS: PTAU was administered orally to mice alone or with uridine. The plasma levels of PTAU as well as those of uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. RESULTS: Co-administration of PTAU with uridine elevated the concentration of plasma uridine in a dose-dependent manner over that resulting from the administration of the same dose of uridine alone, and reduced the clearance of uridine as well as the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Coadministration of PTAU at 30, 45 and 60 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9- and 9.9-fold, respectively, and reduced the AUC of plasma uracil (1227.8 micromol x h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45 and 60 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.8-, 2.6- and 2.8-fold, and that of 660 mg/kg uridine by 2.2-, 2.6- and 3.2-fold, respectively. CONCLUSION: The effectiveness of PTAU in improving the oral bioavailability of uridine could be useful in the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by administration of uridine.     

Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice

As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [(14)C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.     

Plasma pharmacokinetics and bioavailability of 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea after intravenous and oral administration to mice and dogs

PURPOSE: Chloroethylnitrosoureas are among the most widely used chemotherapeutic agents for the treatment of brain tumors. SarCNU (1-(2-chloroethyl)3-sarcosinamide-1-nitrosourea) is an investigational nitrosourea analogue that has shown greater antitumor activity and a more favorable toxicity profile than 1,3-bis(2-chloroethyl)-1-nitrosourea in preclinical studies. The purpose of the present study was to characterize the plasma pharmacokinetics and oral bioavailability of SarCNU in mice and dogs treated by intravenous infusion and gastric intubation. METHODS: SarCNU was administered to mice by i.v. injection or orally at doses ranging from 10 to 100 mg/kg. Plasma samples were obtained from groups of five animals at each time-point at intervals ranging from 3 min to 2.5 h after dosing. A group of three male beagle dogs were treated with Sar CNU 10 mg/kg given both by i.v. infusion and orally in a crossover design. The concentration of SarCNU in plasma was measured by high-performance liquid chromatography. RESULTS: During the initial 90 min after i.v. injection to mice, SarCNU was eliminated from plasma in a monoexponential manner with a mean half-life of 9.8 +/- 0.8 min. The total plasma clearance was 47.3 +/- 8.7 ml/min per kg and the apparent volume of distribution was 0.7 +/- 0.1 l/kg. SarCNU exhibited linear pharmacokinetic behavior following both i.v. and oral administration of doses ranging from approximately 10 to 100 mg/kg. Peak plasma levels provided by a dose of 100 mg/kg given by the i.v. and oral routes were 142.4 microg/ml (0.5 min) and 27.8 microg/ml (9.8 min), respectively. The mean oral bioavailability of the drug was 57.3 +/- 12.6% in mice. In comparison, the disposition of SarCNU in dogs after rapid i.v. injection was biexponential, with half-lives of 5.4 +/- 8.4 min and 40.8 +/- 9.0 min for the initial and terminal disposition phases, respectively. Mean values of the total plasma clearance and apparent volume of distribution were 17.8 +/- 1.8 ml/min per kg and 1.1 +/- 0.3 l/kg, respectively. The Cmax was 18.5 +/- 6.5 microg/ml after i.v. injection and 8.5 0.4 microg/ml after oral administration of a 10 mg/kg dose. Oral bioavailability of the drug in dogs (71.7 +/- 21.2%) was greater than that observed in mice. CONCLUSIONS: SarCNU exhibited linear and consistent pharmacokinetics in mice and dogs with very good oral bioavailability in both species. These findings support the rationale for evaluating SarCNU given by the oral route of administration in phase I clinical trials.     

Medroxyprogesterone acetate bioavailability after high-dose intraperitoneal administration in advanced cancer

Summary Administration of medroxyprogesterone acetate IP in advanced cancer with peritoneal metastases and ascitic effusion generates considerably higher drug plasma levels than those observed after PO or IM treatment. Comparison of areas under the time-concentration curves (AUC) with reference to the three administration routes indicates that after oral administration only 0.2%–17.4% (mean 5.7%; SD 3.77; 40 patients) of the administered dose is absorbed; after IM treatment a daily absorption of 0.7%–7.7% (mean 2.5%; SD 1.66; 30 patients) of the administered dose per injection site was computed.     

Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals.

PURPOSE: Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. Its consumption has been associated with decreased risk of certain types of cancers in humans. The oral bioavailability of the major green tea constituents, green tea catechins, is low, resulting in systemic catechin levels in humans many fold less than the effective concentrations determined in in vitro systems. We conducted this clinical study to test the hypothesis that the oral bioavailability of green tea catechins can be enhanced when consumed in the absence of food. Experimental Designs: Thirty healthy volunteers were randomly assigned to one of the following doses of Polyphenon E (a decaffeinated and defined green tea catechin mixture): 400, 800, or 1,200 mg, based on the epigallocatechin gallate content (10 subjects per dose group). After an overnight fast, study participants took a single dose of Polyphenon E with or without a light breakfast, which consisted of one or two 4-oz muffins and a glass of water. Following a 1-week wash-out period, subjects were crossed over to take the same dose of Polyphenon E under the opposite fasting/fed condition. Tea catechin concentrations in plasma and urine samples collected after dosing were determined by high-pressure liquid chromatography analysis. RESULTS: Consistent with previous reports, epigallocatechin gallate and epicatechin gallate were present in plasma mostly as the free form, whereas epicatechin and epigallocatechin were mostly present as the glucuronide and sulfate conjugates. There was >3.5-fold increase in the average maximum plasma concentration of free epigallocatechin gallate when Polyphenon E was taken in the fasting condition than when taken with food. The dosing condition led to a similar change in plasma-free epigallocatechin and epicatechin gallate levels. Taking Polyphenon E in the fasting state did not have a significant effect on the plasma levels of total (free and conjugated) epigallocatechin, but resulted in lower plasma levels of total epicatechin. Urinary epigallocatechin gallate and epicatechin gallate levels were very low or undetectable following Polyphenon E administration with either dosing condition. Taking Polyphenon E under the fasting state resulted in a significant decrease in the urinary recovery of total epigallocatechin and epicatechin. Polyphenon E administered as a single dose over the dose range studied was generally well-tolerated by the study participants. Mild and transient nausea was noted in some of the study participants and was seen most often at the highest study agent dose (1,200 mg epigallocatechin gallate) and in the fasting condition. CONCLUSIONS: We conclude that greater oral bioavailability of free catechins can be achieved by taking the Polyphenon E capsules on an empty stomach after an overnight fast. Polyphenon E up to a dose that contains 800 mg epigallocatechin gallate is well-tolerated when taken under the fasting condition. This dosing condition is also expected to optimize the biological effects of tea catechins.     

Pharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils in plasma and ascites fluid after oral administration in mice

Summary Pharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils was examined in mice bearing sarcoma 180. The alkylcarbamoyl derivatives were absorbed rapidly as intact form through the gastrointestinal tract and distributed into ascites fluid. Concentration-x-time (C-x-t) values of 5-fluorouracil formed in plasma and ascites fluid decreased in order by extension of the carbon chain of the alkyl moiety. C-x-t value of 5-fluorouracil formed in ascites fluid after hexylcarbamoyl derivative was higher than that in plasma. Antitumor activity of the compounds was correlated with both maximum concentration (Cmax) and C-x-t values of 5-fluorouracil formed and Cmax of total (intact form plus 5-fluorouracil formed) in ascites fluid (P<0.01), and with C-x-t values in ascites fluid and Cmax and C-x-t values of 5-fluorouracil formed in plasma (P<0.05). Alkylcarbamoyl structure was valuable for rapid absorption through the gastrointestinal tract and blood-ascites barrier and for maintenance of 5-fluorouracil level in plasma and ascites fluid.     

Hepatocarcinogenicity of the herbicide maleic hydrazide following parenteral administration to infant Swiss mice

Random-bred infant Swiss mice were injected subcutaneously with maleic hydrazide in aqueous solution or tricaprylin suspension in varying doses. Maleic hydrazide in excess of 0.5 mg on the first day of life was lethal. Following a total maleic hydrazide dosage of 55 mg in the first 3 weeks of life, there was a high incidence of hepatomas, 65% of 26 male mice alive at 49 weeks, in contrast to solvent controls, 8% of 48 male mice. On the basis of these data, it is necessary to consider the possibility of carcinogenic hazard to man due to exposure to maleic hydrazide residues in root crops and tobacco.     

Reduction in plasma or skin alpha-tocopherol concentration with long-term oral administration of beta-carotene in humans and mice.

BACKGROUND: Beta-carotene is one of the most commonly used compounds in clinical trials of chemopreventive agents in various neoplastic diseases. Animal studies, including our own, have documented that dietary beta-carotene can reduce plasma alpha-tocopherol (vitamin E) levels, but few published studies have examined the clinical or pharmacokinetic ramifications of long-term, high-dose beta-carotene regimens on other fat-soluble vitamins such as alpha-tocopherol. PURPOSE: This study was designed to determine the effects of long-term beta-carotene supplementation on plasma concentrations of alpha-tocopherol in normal human subjects and in an experimental C3H/HeN mouse model. METHODS: In a double-blind study, 45 normal subjects were randomly assigned to receive 0 (placebo), 15, 30, 45, or 60 mg of oral beta-carotene daily for approximately 9 months. Monthly plasma samples were collected. Thirty-five C3H/HeN mice were fed a basal diet with or without beta-carotene and treated topically with or without alpha-tocopherol, except for the control mice, which received UV radiation for 27 weeks from week 3 to week 30. Plasma and dorsal skin samples were taken after 40 weeks and were analyzed for alpha-tocopherol and/or beta-carotene by high-performance liquid chromatography. RESULTS: Long-term dietary beta-carotene administration resulted in statistically significant reductions in levels of alpha-tocopherol in the skin and plasma of UV-irradiated mice. In the human study, the decrease in plasma alpha-tocopherol levels was progressive and significant between 6 and 9 months of beta-carotene dosing in all dosage groups. The greatest decrease was observed during the 9th (last) month of dosing, with a decrease of 40% from baseline. All oral beta-carotene doses (15-60 mg/d), however, resulted in similar decreases in steady-state plasma levels of alpha-tocopherol and in only small differences in beta-carotene plasma levels. CONCLUSION: Long-term oral administration of beta-carotene decreased steady-state plasma concentrations of alpha-tocopherol. The lack of a significant dose-response effect between doses of beta-carotene and alpha-tocopherol plasma levels is not unexpected, given the small differences in steady-state beta-carotene plasma levels in the four beta-carotene dose groups. IMPLICATIONS: Studies are needed to determine how long-term beta-carotene dosing influences tissue distribution of dietary alpha-tocopherol. Careful surveillance for this and other potentially harmful nutrient interactions should become part of all long-term intervention studies.     

Comparison of the pharmacokinetics and efficacy of irinotecan after administration by the intravenous versus intraperitoneal route in mice

Irinotecan (CPT-11) is a new drug active in colorectal cancer. A comparison was made of the efficacy and pharmacokinetics of CPT-11 after i.p. versus i.v. administration to mice. We found that i.p. administration of CPT-11 to mice bearing C26 colon cancer was more efficient and less toxic than i.v. administration; a 100-mg i.p. dose induced an increase in life span equivalent to that produced by a 300-mg i.v. dose, and toxic deaths appeared after doses of 400 mg/kg given i.v. and 800 mg/kg given i.p. Pharmacokinetic parameters of CPT-11 and SN-38 were compared after i.v. or i.p. administration in mice bearing P388 leukemia ascites. Peritoneal CPT-11 and SN-38 AUC values were higher after i.p. administration than after i.v. injection. Plasmatic AUC values remained equivalent. Moreover, peritoneal CPT-11 clearance was 10-fold lower after i.p. versus i.v. administration. If the survival and pharmacologic advantage of i.p. CPT-11 in the murine model considered can be translated to a safe and practical mode of therapy in patients and if local toxicity does not prove to be a major adverse effect, then a potentially useful agent could be added to the drugs known to be active when given by the i.p. route for adjuvant therapy in colon cancer. Received: 21 October 1997 / Accepted: 12 December 1997     

5-(Phenylthio)acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens

Purpose The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the pharmacokinetics and bioavailability of oral uridine. PTAU is a potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is fully absorbed after oral administration with 100% oral bioavailability.Methods Uridine (330, 660 or 1320 mg/kg) and/or PTAU (30, 45, 60, 120, 240 or 480 mg/kg) were orally administered to mice. The plasma levels of uridine, its catabolite uracil, and PTAU were measured using HPLC, and pharmacokinetic analysis was performed.Results Oral PTAU up to 480 mg/kg per day is not toxic to mice. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg has a prolonged plasma half-life of 2–3 h, and peak plasma PTAU concentrations (C_max) of 41, 51, 74, 126 and 161 M with AUCs of 70, 99, 122, 173 and 225 mol h/l, respectively. Coadministration of uridine with PTAU did not have a significant effect on the pharmacokinetic parameters of plasma PTAU at any of the doses tested. Coadministration of PTAU (30, 45, 60 and 120 or 240 mg/kg) with uridine (330, 660 or 1320 mg/kg) elevated the concentration of plasma uridine over that following the same dose of uridine alone, a result of reduced metabolic clearance of uridine as evidenced by decreased plasma exposure (C_max and AUC) to uracil. Plasma uridine was elevated with the increase of uridine dose at each PTAU dose tested and no plateau was reached. Coadministration of PTAU at 30, 45, 60, 120 and 240 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9-, 9.9-, 11.7- and 12.5-fold, respectively, and reduced the AUC of plasma uracil (1227.8 mol h/l) by 5.7-, 6.8-, 8.2-, 6.3-, and 6.9-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45, 60, 120 and 240 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.7-, 2.4-, 2.6-, 5.2- and 4.3- fold, and that of 660 mg/kg uridine by 2.3-, 2.7-, 3.3-, 4.6- and 6.7-fold, respectively.Conclusion The excellent pharmacokinetic properties of PTAU, and its extraordinary effectiveness in improving the oral bioavailability of uridine, could be useful to rescue or protect from host toxicities of 5-fluorouracil and various chemotherapeutic pyrimidine analogues used in the treatment of cancer and AIDS, as well as in the management of medical disorders that are remedied by the administration of uridine including CNS disorders (e.g. Huntingtons disease, bipolar disorder), liver diseases, diabetic neuropathy, cardiac damage, various autoimmune diseases, and transplant rejection.     

Comparison of liver tumor frequencies after intermittent oral administration of different doses of N-nitrosopyrrolidine in Sprague-Dawley rats

N-Nitrosopyrrolidine (N-Pyr) was administered orally to 400 Sprague-Dawley rats. An additional group of 80 rats served as an untreated control. There were 5 individual groups in which the effects of different periods of dosing and varying intervals without treatment were compared. Individual doses corresponded to 0.0, 1.0, 1.2 and 2.0 mg/kg per day. The total dose (600 days after the start of the trial) always amounted to 600 mg/kg N-Pyr. Significantly different incidences of liver tumors were observed in the individual N-Pyr-treated groups. The findings support the assumption that tumor risks not only depend on individual and total doses of the administered carcinogen, but are also an age-related function.