Bibliothek

Notizen: Abstract  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.

Notizen: Abstract 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 μCi3H-uridine. Administration of3H-uridine alone led to its rapid catabolism to uracil and dihydrouracil. Administration of 83.3 mg/kg BAU with 500 μCi3H-uridine resulted in a 2.5-fold enhancement of3H-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.

Notizen: The photodissociation dynamics of some organometallic molecules in the lowest repulsive electronically states are reported for the following concurrent primary reactions: (i) the homolysis of a metal-hydrogen bond vs. the heterolytic loss of a carbonyl ligand in HCo(CO)4; (ii) the photoinduced elimination of molecular hydrogen vs. the loss of a carbonyl ligand in H2Fe(CO)4; and (iii) the photoinduced elimination of molecular hydrogen vs. the loss of a mesithylene ligand in H2Os(CO)Mes (Mes = C6H3(CH3))3. The dynamics are simulated quantum mechanically using a time-dependent wavepacket propagation technique on potential energy surfaces obtained from CASSCF/CCI calculations for HCo(CO)4 and H2Fe(CO)4 and from SCF-INO/MRCI calculations for H2Os(CO)Mes. This approach gives a rather detailed view of some important elementary processes that contribute to the photochemistry of these complexes. The nature of the photoactive excited states is determined without ambiguity, as well as the time scales, the branching ratio of the different primary dissociation pathways, and some features of the absorption spectra. © 1994 John Wiley & Sons, Inc.

Notizen: Three specific model systems, HCo(CO)4, Na · NH3, and NO/Pt(111), are used to extend the strategy of vibrationally mediated photodissociations of organometallics, via small clusters of metal atoms and small molecules, to photodesorption of small molecules from metal surfaces. All systems and strategies are similar with respect to breaking metal-ligand bonds by means of infrared IR and visible or ultraviolet UV photons. Specific properties of the systems call, however, for different implementations of the overall tools. In the case of HCo(CO)4, traditional continuous wave (CW) IR + UV 2-photon excitations enhance the rates of HCo bond homolysis. A detailed analysis discovers three effects which result from Franck-Condon transitions in the domains of vibrationally excited wave functions: (i) ultrafast (≈ 20 fs) bond rupture starting from the steeply repulsive wall of the potential energy surface of the excited singlet state; (ii) efficient fast (≈ 200 fs) predissociation via tunneling through neighboring potential barriers; and (iii) decreasing contributions from indirect dissociations via slow (≈ 46 ps) intersystem crossing induced by spin-orbit coupling. In the case of Na · NH3, we suggest a vibrationally mediated pump-and-dump scheme, similar to the strategy of Tannor, Rice, and Kosloff, with proper control of the delay (ca. 70 fs) between ultrashort (ca. 30 fs) pump-and-dump laser pulses. Ultimately, this strategy shifts specific lobes of the vibrationally excited wave packets into a steeply repulsive wall of the potential energy surface of the electronic ground state, with subsequent fast (ca. 100 fs) ruptures of the NA(SINGLEBOND)NH3 bond, similar to effect (i) for HCo(CO)4. Finally, we show that a similar, vibrationally mediated pump-and-dump scheme may also support photodesorption of NO from Pt(111), with an intrinsic relaxation step for the electronically excited system NO/Pt(111) instead of active pump-and-dump control for Na · NH3. All strategies are simulated by fast Fourier transform propagations of representative wave packets on two potential energy surfaces. © 1996 John Wiley & Sons, Inc.