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K A Duggan - One of the best experts on this subject based on the ideXlab platform.
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uridine kinase inhibition is involved in the vasodilator effects of minoxidil in the rat
Clinical and Experimental Pharmacology and Physiology, 1990Co-Authors: G J Macdonald, Therese Walker, Rhonda Assef, K A DugganAbstract:SUMMARY 1. Since minoxidil is a pyrimidine derivative, its actions on vascular smooth muscle may derive from structural relationships to the uridine nucleotides, which have been shown to be vasoconstrictive in the rat. 2. Minoxidil at a low vasodepressor dose of 0.03 mg/kg per min abolished the pressor response to uridine at doses from 2 to 8 μmol/kg per min, but did not reduce the responses to uridine monophosphate or uridine diphosphate in similar pressor doses, suggesting an action on either transport of uridine into cells or on uridine kinase which catalyses phosphorylation of uridine to uridine monophosphate, the mediator of uridine's vascular actions. 3. The active metabolite of minoxidil was found to inhibit rat liver uridine kinase in vivo using an HPLC technique. 4. Plasma uridine concentration was significantly higher in 11 hypertensive patients on minoxidil compared with pretreatment values, suggesting that uridine kinase inhibition is of a degree sufficient to increase the circulating pool of uridine. 5. The data is consistent with uridine kinase inhibition being a mechanism for the vasodilator actions of minoxidil.
Mahmoud H. Kouni - One of the best experts on this subject based on the ideXlab platform.
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5-(Phenylthio)acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Omar N. Al Safarjalani, Fardos N.m. Naguib, Xiao-jian Zhou, Raymond F. Schinazi, Reem H. Rais, Mahmoud H. KouniAbstract: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 μ M with AUCs of 70, 99, 122, 173 and 225 μmol 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 μmol 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. Huntington’s disease, bipolar disorder), liver diseases, diabetic neuropathy, cardiac damage, various autoimmune diseases, and transplant rejection.
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Effects of 5-benzylacyclouridine, an inhibitor of uridine phosphorylase, on the pharmacokinetics of uridine in rhesus monkeys: implications for chemotherapy.
Cancer chemotherapy and pharmacology, 1995Co-Authors: Jean Pierre Sommadossi, Erika M. Cretton, Lauren B. Kidd, Daniel C. Anderson, Harold M Mcclure, Mahmoud H. KouniAbstract:The effects of subcutaneous administration of 5-benzylacyclouridine (BAU), a uridine phosphorylase (UrdPase, EC 2.4.2.3) inhibitor, on uridine concentration in plasma and urine were evaluated in rhesus monkeys. Administration of BAU at 50, 100 and 250 mg/kg increased the plasma uridine baseline concentration 1.5-, 2.9-, and 3.2-fold, respectively. The basis for this moderate perturbation of plasma uridine by BAU was investigated using a tracer dose of 500 microCi 3H-uridine. Administration of 3H-uridine alone led to its rapid catabolism to uracil and dihydrouracil. Administration of 83.3 mg/kg BAU with 500 microCi 3H-uridine resulted in a 2.5-fold enhancement of 3H-uridine plasma levels and a substantial decrease in the plasma levels of uridine catabolites, suggesting inhibition of UrdPase activity by BAU in rhesus monkeys. Coadministration of 83.3 mg/kg BAU with 83.3 mg/kg uridine also reduced the plasma concentration of uracil and dihydrouracil, but it did not increase plasma uridine concentration above that of control animals receiving 83.3 mg/kg uridine alone. In animals receiving uridine alone at 83.3 or 25 mg/kg, approximately 10% of the administered dose was recovered in the urine within 6 h, with unchanged uridine being the major component. In contrast, administration of 83.3 mg/kg BAU increased the excretion of unchanged uridine to more than 32% of the total dose administered, even when the urinary excretion ratio of uracil to uridine was reduced ten-fold. Administration of multiple doses (three times per day) of BAU alone (83.3 mg/kg) or in the presence of uridine (83.3 mg/kg) did not enhance plasma uridine concentration further. In addition, uridine pharmacokinetics were associated with a time-dependent relationship as evidenced by an increased total plasma clearance, renal clearance and volume of distribution, resulting in a substantial decrease in uridine peak concentration with time. These results indicate that administration of BAU inhibits UrdPase activity in rhesus monkeys as manifested by decreased uracil and dihydrouracil plasma levels, as well as a lower urinary excretion ratio of uracil to uridine, as compared to control animals. However, plasma levels of unchanged uridine were not substantially enhanced by BAU in spite of the large increase in urinary excretion of unchanged uridine. This phenomenon was also observed when uridine was coadministered with BAU, suggesting that plasma uridine concentration in monkeys may be strongly regulated by the renal system as evidenced by the "spillover" of excess plasma uridine into urine. In addition, the pharmacokinetics of uridine were dose-independent, but time-dependent.(ABSTRACT TRUNCATED AT 400 WORDS)
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Effects of 5-benzylacyclouridine, an inhibitor of uridine phosphorylase, on the pharmacokinetics of uridine in rhesus monkeys: implications for chemotherapy
Cancer Chemotherapy and Pharmacology, 1995Co-Authors: Jean Pierre Sommadossi, Erika M. Cretton, Lauren B. Kidd, Daniel C. Anderson, Harold M Mcclure, Mahmoud H. KouniAbstract:The effects of subcutaneous administration of 5-benzylacyclouridine (BAU), a uridine phosphorylase (UrdPase, EC 2.4.2.3) inhibitor, on uridine concentration in plasma and urine were evaluated in rhesus monkeys. Administration of BAU at 50, 100 and 250 mg/kg increased the plasma uridine baseline concentration 1.5-, 2.9-, and 3.2-fold, respectively. The basis for this moderate perturbation of plasma uridine by BAU was investigated using a tracer dose of 500 μCi^3H-uridine. Administration of^3H-uridine alone led to its rapid catabolism to uracil and dihydrouracil. Administration of 83.3 mg/kg BAU with 500 μCi^3H-uridine resulted in a 2.5-fold enhancement of^3H-uridine plasma levels and a substantial decrease in the plasma levels of uridine catabolites, suggesting inhibition of UrdPase activity by BAU in rhesus monkeys. Coadministration of 83.3 mg/kg BAU with 83.3 mg/kg uridine also reduced the plasma concentration of uracil and dihydrouracil, but it did not increase plasma uridine concentration above that of control animals receiving 83.3 mg/kg uridine alone. In animals receiving uridine alone at 83.3 or 25 mg/kg, approximately 10% of the administered dose was recovered in the urine within 6 h, with unchanged uridine being the major component. In contrast, administration of 83.3 mg/kg BAU increased the excretion of unchanged uridine to more than 32% of the total dose administered, even when the urinary excretion ratio of uracil to uridine was reduced ten-fold. Administration of multiple doses (three times per day) of BAU alone (83.3 mg/kg) or in the presence of uridine (83.3 mg/kg) did not enhance plasma uridine concentration further. In addition, uridine pharmacokinetics were associated with a time-dependent relationship as evidenced by an increased total plasma clearance, renal clearance and volume of distribution, resulting in a substantial decrease in uridine peak concentration with time. These results indicate that administration of BAU inhibits UrdPase activity in rhesus monkeys as manifested by decreased uracil and dihydrouracil plasma levels, as well as a lower urinary excretion ratio of uracil to uridine, as compared to control animals. However, plasma levels of unchanged uridine were not substantially enhanced by BAU in spite of the large increase in urinary excretion of unchanged uridine. This phenomenon was also observed when uridine was coadministered with BAU, suggesting that plasma uridine concentration in monkeys may be strongly regulated by the renal system as evidenced by the “spillover” of excess plasma uridine into urine. In addition, the pharmacokinetics of uridine were dose-independent, but time-dependent. This investigation may provide insights into the clinical usefulness of BAU to protect against or rescue from host toxicity induced by FUra and other chemotherapeutic pyrimidine analogues whose toxicity can be alleviated by uridine.
Piero Luigi Ipata - One of the best experts on this subject based on the ideXlab platform.
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Metabolic interplay between intra- and extra-cellular uridine metabolism via an ATP driven uridine-UTP cycle in brain.
The International Journal of Biochemistry & Cell Biology, 2010Co-Authors: Piero Luigi Ipata, Marcella Camici, Catia Barsotti, Maria Grazia Tozzi, Francesco BalestriAbstract:Abstract Uridine, a pyrimidine nucleoside essential for the synthesis of RNA and biomembranes, has several trophic functions in the central nervous system, that involve a physiological regulation of pyrimidine nucleotides and phospholipids content, and a maintenance of brain metabolism under ischemia, or pathological situations. The understanding of uridine production in the brain is therefore of fundamental importance. Brain has a limited capacity to synthesize ex novo the pyrimidine ring, and a reasonable source of brain uridine is UTP. The kinetics of UTP breakdown, as catalysed by post-mitochondrial brain extracts and membrane preparations reported herein suggests that in normoxic conditions uridine is locally generated in brain exclusively in the extracellular space, and that any uptaken uridine is salvaged to UTP. It is now well established that cytosolic UTP can be released to interact with a subset of P2Y receptors, inducing a variety of molecular and cellular effects, leading to neuroprotection, while uridine is uptaken via an equilibrative or a Na+-dependent transport system, to exert its trophic effects in the cytosol. An ATP driven uridine–UTP cycle can be envisaged, based on the strictly compartmentalized processes of uridine salvage to UTP and uridine generation from UTP, in which uptaken uridine is anabolised to UTP in the cytosol, and converted back to uridine in extracellular space.
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key role of uridine kinase and uridine phosphorylase in the homeostatic regulation of purine and pyrimidine salvage in brain
Neurochemistry International, 2007Co-Authors: Francesco Balestri, Catia Barsotti, Ludovico Lutzemberger, Marcella Camici, Piero Luigi IpataAbstract:Abstract Uridine, the major circulating pyrimidine nucleoside, participating in the regulation of a number of physiological processes, is readily uptaken into mammalian cells. The balance between anabolism and catabolism of intracellular uridine is maintained by uridine kinase, catalyzing the first step of UTP and CTP salvage synthesis, and uridine phosphorylase, catalyzing the first step of uridine degradation to β-alanine in liver. In the present study we report that the two enzymes have an additional role in the homeostatic regulation of purine and pyrimidine metabolism in brain, which relies on the salvage synthesis of nucleotides from preformed nucleosides and nucleobases, rather than on the de novo synthesis from simple precursors. The experiments were performed in rat brain extracts and cultured human astrocytoma cells. The rationale of the reciprocal regulation of purine and pyrimidine salvage synthesis in brain stands (i) on the inhibition exerted by UTP and CTP, the final products of the pyrimidine salvage pathway, on uridine kinase and (ii) on the widely accepted idea that pyrimidine salvage occurs at the nucleoside level (mostly uridine), while purine salvage is a 5-phosphoribosyl-1-pyrophosphate (PRPP)-mediated process, occurring at the nucleobase level. Thus, at relatively low UTP and CTP level, uptaken uridine is mainly anabolized to uridine nucleotides. On the contrary, at relatively high UTP and CTP levels the inhibition of uridine kinase channels uridine towards phosphorolysis. The ribose-1-phosphate is then transformed into PRPP, which is used for purine salvage synthesis.
Mahmoud H. El Kouni - One of the best experts on this subject based on the ideXlab platform.
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Uridine prevents the glucose deprivation-induced death of immunostimulated astrocytes via the action of uridine phosphorylase
Neuroscience Research, 2006Co-Authors: Ji Woong Choi, Mahmoud H. El Kouni, Chan Young Shin, Kwang Ho KoAbstract:We previously reported that in immunostimulated astrocytes, glucose deprivation induced cell death via the loss of ATP, reduced glutathione, and mitochondrial transmembrane potential. The cytotoxicity was due to reactive nitrogen and oxygen species and blocked by adenosine, a purine nucleoside, via the preservation of cellular ATP. Here, we investigated whether uridine, a pyrimidine nucleoside, could prevent the glucose deprivation-induced cytotoxicity in LPS + IFN-γ-treated (immunostimulated) astrocytes. Glucose deprivation induced the death of immunostimulated cells, which was significantly reduced by uridine. Glucose deprivation rapidly decreased cellular ATP levels in immunostimulated astrocytes, which was also reversed by uridine. The inhibition of cellular uptake of uridine by S-(4-nitrobenzyl)-6-thioinosine attenuated the protective effect of uridine. mRNA and protein expression for uridine phosphorylase, an enzyme catalyzing reversible phosphorolysis of uridine, were observed in rat brain as well as primary astrocytes. 5-(Phenylthio)acyclouridine (PTAU), a specific inhibitor of uridine phosphorylase, inhibited the protective effect of uridine. Additionally, the loss of mitochondrial transmembrane potential and reduced glutathione by glucose deprivation in immunostimulated cells was attenuated by uridine, which was also reversed by PTAU. These results provide the first evidence that uridine protects immunostimulated astrocytes against the glucose deprivation-induced death by preserving intracellular ATP through the action of uridine phosphorylase.
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Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: implications for uridine rescue regimens in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2001Co-Authors: Omar N. Al Safarjalani, Fardos N.m. Naguib, Xiao-jian Zhou, Raymond F. Schinazi, Mahmoud H. El KouniAbstract: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: Coadministration 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 µmol·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.
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Effect of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on plasma concentration of uridine released from 2',3',5'-tri-O-acetyluridine, a prodrug of uridine: relevance to uridine rescue in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Raymond F. Schinazi, Naganna M. Goudgaon, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acyclouridine (PSAU) with 2′,3′,5′-tri-O-acetyluridine (TAU) on the levels of plasma uridine in mice. PSAU is a new lipophilic and potent inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral uridine. TAU is a prodrug of uridine and a far superior source of uridine than uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the Cmax and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma uridine concentration could be useful in the management of medical disorders that are remedied by administration of uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues.
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Modulation of plasma uridine concentration by 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase: relevance to chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Omar N. Al Safarjalani, Raymond F. Schinazi, Naganna M. Goudgaon, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acyclouridine (PSAU) in increasing endogenous plasma uridine concentration as well as its ability to improve the bioavailability of oral uridine. PSAU 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. Methods: Oral PSAU was administered orally to mice alone or with uridine. The plasma levels of PSAU as well as uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. Results: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma uridine (2.6 ± 0.7 μM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with uridine elevated the concentration of plasma uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral uridine (7.7%) administered at 1320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1421 to 787 μmol/h · l and 273 μmol/h · l, respectively. Similar results were observed when PSAU was co-administered with lower doses of uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1320 mg/kg uridine was used. Conclusion: The effectiveness of the PSAU plus uridine combination in elevating and sustaining high plasma uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of uridine.
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5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy.
Biochemical Pharmacology, 1996Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent inhibitor known of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism, and 2',3',5'-tri-O-acetyluridine (TAU), a prodrug of uridine, were used to investigate the possibility of improving the bioavailability of oral uridine in mice. Oral BBBA administered at 30, 60, 120, and 240 mg/kg increased the concentration of plasma uridine (2.6 +/- 0.7 microM) by 3.2-, 4.6-, 5.4-, and 7.2-fold, respectively. After administration of 120 and 240 mg/kg BBBA, plasma uridine concentration remained 3- and 6-fold, respectively, higher than the plasma concentration at zero time (C0) for over 8 hr. On the other hand, BBBA did not change the concentration of plasma uracil. TAU was far more superior than uridine in improving the bioavailability of plasma uridine. The relative bioavailability of plasma uridine released from oral TAU (53%) was 7-fold higher than that (7.7%) obtained by oral uridine. Oral TAU at 460, 1000, and 2000 mg/kg achieved area under the curve (AUC) values of plasma uridine of 82, 288, and 754 mumol.hr/L, respectively. Coadministration of BBBA with uridine or TAU further improved the bioavailability of plasma uridine resulting from the administration of either alone and reduced the Cmax and AUC of plasma uracil. Coadministration of BBBA at 30, 60, and 120 mg/kg improved the relative bioavailability of uridine released from 2000 mg/kg TAU (53%) by 1.7-, 2.7-, and 3.9-fold, respectively, while coadministration of the same doses of BBBA with an equimolar dose of uridine (1320 mg/kg) increased the relative bioavailability of oral uridine (7.7%) by 4.1-, 5.3-, and 7.8-fold, respectively. Moreover, the AUC and Cmax of plasma uridine after BBBA (120 mg/kg) coadministration with TAU were 3.5- and 11.5-fold, respectively, higher than those obtained from coadministration of BBBA with an equimolar dose of uridine. The exceptional effectiveness of the BBBA plus TAU combination in elevating and sustaining high plasma uridine concentration can be useful in the management of medical disorders that are remedied by administration of uridine as well as to rescue or protect from host-toxicities of various chemotherapeutic pyrimidine analogues.
Fardos N.m. Naguib - One of the best experts on this subject based on the ideXlab platform.
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5-(Phenylthio)acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Omar N. Al Safarjalani, Fardos N.m. Naguib, Xiao-jian Zhou, Raymond F. Schinazi, Reem H. Rais, Mahmoud H. KouniAbstract: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 μ M with AUCs of 70, 99, 122, 173 and 225 μmol 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 μmol 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. Huntington’s disease, bipolar disorder), liver diseases, diabetic neuropathy, cardiac damage, various autoimmune diseases, and transplant rejection.
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Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: implications for uridine rescue regimens in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2001Co-Authors: Omar N. Al Safarjalani, Fardos N.m. Naguib, Xiao-jian Zhou, Raymond F. Schinazi, Mahmoud H. El KouniAbstract: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: Coadministration 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 µmol·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.
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Effect of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on plasma concentration of uridine released from 2',3',5'-tri-O-acetyluridine, a prodrug of uridine: relevance to uridine rescue in chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Raymond F. Schinazi, Naganna M. Goudgaon, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acyclouridine (PSAU) with 2′,3′,5′-tri-O-acetyluridine (TAU) on the levels of plasma uridine in mice. PSAU is a new lipophilic and potent inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral uridine. TAU is a prodrug of uridine and a far superior source of uridine than uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the Cmax and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma uridine concentration could be useful in the management of medical disorders that are remedied by administration of uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues.
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Modulation of plasma uridine concentration by 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase: relevance to chemotherapy.
Cancer Chemotherapy and Pharmacology, 2000Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Omar N. Al Safarjalani, Raymond F. Schinazi, Naganna M. Goudgaon, Mahmoud H. El KouniAbstract:Purpose: The purpose of this investigation was to evaluate the efficacy of oral 5-(phenylselenenyl)-acyclouridine (PSAU) in increasing endogenous plasma uridine concentration as well as its ability to improve the bioavailability of oral uridine. PSAU 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. Methods: Oral PSAU was administered orally to mice alone or with uridine. The plasma levels of PSAU as well as uridine and its catabolites were measured using high-performance liquid chromatography and pharmacokinetic analysis was performed. Results: PSAU has an oral bioavailability of 100% and no PSAU metabolites were detected. PSAU has no apparent toxicity at high doses. Oral administration of PSAU at 30 and 120 mg/kg increased baseline concentration of endogenous plasma uridine (2.6 ± 0.7 μM) by 3.2- and 8.7-fold, respectively, and remained three- and six-fold higher, respectively, than the controls for over 8 h. PSAU, however, did not alter the concentration of endogenous plasma uracil. Co-administration of PSAU with uridine elevated the concentration of plasma uridine over that resulting from the administration of either alone, and reduced the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Co-administration of PSAU at 30 mg/kg and 120 mg/kg improved the low bioavailability of oral uridine (7.7%) administered at 1320 mg/kg by 4.8- and 4.2-fold, respectively, and reduced the AUC of plasma uracil from 1421 to 787 μmol/h · l and 273 μmol/h · l, respectively. Similar results were observed when PSAU was co-administered with lower doses of uridine. Oral PSAU at 30 mg/kg and 120 mg/kg improved the bioavailability of oral 330 mg/kg uridine by 5.2- and 8.9-fold, and that of oral 660 mg/kg uridine by 6.4- and 9.0-fold, respectively. However, the reduction in the AUC values of plasma uracil was less dramatic than that seen when the high dose of 1320 mg/kg uridine was used. Conclusion: The effectiveness of the PSAU plus uridine combination in elevating and sustaining high plasma uridine concentration may be useful to rescue or protect from host toxicity of various chemotherapeutic pyrimidine analogs as well as in the management of medical disorders that are remedied by administration of uridine.
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5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy.
Biochemical Pharmacology, 1996Co-Authors: Osama M. Ashour, Fardos N.m. Naguib, Mahmoud H. El KouniAbstract:5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent inhibitor known of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism, and 2',3',5'-tri-O-acetyluridine (TAU), a prodrug of uridine, were used to investigate the possibility of improving the bioavailability of oral uridine in mice. Oral BBBA administered at 30, 60, 120, and 240 mg/kg increased the concentration of plasma uridine (2.6 +/- 0.7 microM) by 3.2-, 4.6-, 5.4-, and 7.2-fold, respectively. After administration of 120 and 240 mg/kg BBBA, plasma uridine concentration remained 3- and 6-fold, respectively, higher than the plasma concentration at zero time (C0) for over 8 hr. On the other hand, BBBA did not change the concentration of plasma uracil. TAU was far more superior than uridine in improving the bioavailability of plasma uridine. The relative bioavailability of plasma uridine released from oral TAU (53%) was 7-fold higher than that (7.7%) obtained by oral uridine. Oral TAU at 460, 1000, and 2000 mg/kg achieved area under the curve (AUC) values of plasma uridine of 82, 288, and 754 mumol.hr/L, respectively. Coadministration of BBBA with uridine or TAU further improved the bioavailability of plasma uridine resulting from the administration of either alone and reduced the Cmax and AUC of plasma uracil. Coadministration of BBBA at 30, 60, and 120 mg/kg improved the relative bioavailability of uridine released from 2000 mg/kg TAU (53%) by 1.7-, 2.7-, and 3.9-fold, respectively, while coadministration of the same doses of BBBA with an equimolar dose of uridine (1320 mg/kg) increased the relative bioavailability of oral uridine (7.7%) by 4.1-, 5.3-, and 7.8-fold, respectively. Moreover, the AUC and Cmax of plasma uridine after BBBA (120 mg/kg) coadministration with TAU were 3.5- and 11.5-fold, respectively, higher than those obtained from coadministration of BBBA with an equimolar dose of uridine. The exceptional effectiveness of the BBBA plus TAU combination in elevating and sustaining high plasma uridine concentration can be useful in the management of medical disorders that are remedied by administration of uridine as well as to rescue or protect from host-toxicities of various chemotherapeutic pyrimidine analogues.
