PubMed · 15909009
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Olav Spigset, Lars Slørdal. 2005-05-19. [Basic pharmacokinetics--balance].. https://pubmed.ncbi.nlm.nih.gov/15909009/
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In this contribution quantum/classical surface hopping methodology is applied to vibrational energy relaxation of a quantum oscillator in a classical heat bath. The model of a linearly damped (harmonic) oscillator is chosen which can be mapped onto the Brownian motion (Caldeira-Leggett) Hamiltonian. In the simulations Tully's fewest switches surface hopping scheme is adopted with inclusion of dephasing in the adiabatic basis using a simple decoherence algorithm. The results are compared to the predictions of a Redfield-type quantum master equation modeling using the classical heat bath force correlation function as input. Thereby a link is established between both types of quantum/classical approaches. Viewed from the latter perspective, surface hopping with dephasing may be interpreted as "on-the-fly" stochastic realization of a quantum/classical Pauli master equation.
As part of an ongoing phase 1 study, we studied the excretion of XK469 and its metabolism in patients and in vitro. Five primary metabolites were identified by HPLC/MS/MS. An oxidized product formed by cytosolic aldehyde oxidase was the predominant species both in urine and human hepatocytes in vitro. Conjugates of XK469 with glycine, taurine, and glucuronic acid, as well as the microsomal product, 4-oxo-XK469, were also found in urine and in vitro, but none were major contributors to the mass balance for XK469 elimination. Based upon the relative concentrations circulating in plasma, systemic exposure to parent drug was 100-fold higher than for the metabolites. Thus, both toxicity and efficacy of XK469 are most likely to be produced by the parent molecule, rather than the metabolites. Urinary recovery of parent drug was low (2% of dose in 24 h), partly because of the long half-life of XK469 (approximately 3 days). In addition, the metabolite profile in urine indicates that only 25% of the XK469-derived material was unchanged drug. Thus, urinary excretion was not a major factor in XK469 elimination. Variations in systemic exposure to XK469 will be strongly influenced by factors that alter the activity of aldehyde oxidase, including pharmacogenetics, enzyme inhibition, and enzyme induction, but no specific modifiers have been reported. The multiday half-life of XK469 hampered our ability to obtain a complete mass balance, and the possibility exists that other routes, such as biliary excretion, may also play a substantial role in XK469 disposition.
The mechanism of the spontaneous decomposition of 3-bromo-2,2-bis(bromomethyl)propanol (TBNPA) and the kinetics of the reaction of the parent compound and two subsequent products were determined in aqueous solution at temperatures from 30 to 70 degrees C and pH from 7.0 to 9.5. TBNPA is decomposed by a sequence of reactions that form 3,3-bis(bromomethyl)oxetane (BBMO), 3-bromomethyl-3-hydroxymethyloxetane (BMHMO), and 2,6-dioxaspiro[3.3]-heptane (DOH), releasing one bromide ion at each stage. The pseudo-first-order rate constant of the decomposition of TBNPA increases linearlywith the pH. The apparent activation energy of this transformation (98+/-2 KJ/mol) was calculated from the change of the effective second-order rate constant with temperature. The pseudoactivation energies of BBMO and BMHMO were estimated to be 109 and 151 KJ/mol, respectively. Good agreement was found between the rate coefficients derived from changes in the organic molecules concentrations and those determined from the changes in the Br- concentrations. TBNPA is the most abundant semivolatile organic pollutant in the aquitard studied, and together with its byproducts they posess an environmental hazard. TBNPA half-life is estimated to be about 100 years. This implies that high concentrations of TBNPA will persist in the aquifer long after the elimination of all its sources.