Pharmacokinetics stereoselective

Isley WL, Oki JC (2000) Rosiglitazone and liver failure. Ann Intern Med 133 393 Izumi T, Enomoto S, Hoshiyama K, Sasahara K, Sugiyama Y (1997a) Pharmacokinetic stereoselectivity of troglitazone, an antidiabetic agent, in the KK mouse. Biophaim Drug Dispos... 

Dexrazoxane was also hydrolyzed enzymatically in the liver and kidney by dihydropyrimidine aminohydrolase. This enzyme could hydrolyze one but not a second ring of this molecule. Levrazoxane, the enantiomer of dexrazoxane, was also hydrolyzed enzymatically by DHPase in liver homogenates, but at a rate 4.5-fold slower [136], However, in vivo studies in rats dosed with razoxane (the racemic mixture of levrazoxane and dexrazoxane) revealed only a relatively small difference in elimination of the two enantiomers. This suggests that distribution and excretion reduced the impact of stereoselective biotransformation on the pharmacokinetics of these two enantiomers [137]. 

T. Itoh, H. Yamada, Diastereomeric /3-Lactam Antibiotics. Analytical Methods, Isomerization and Stereoselective Pharmacokinetics , J. Chromatogr., A 1995, 694, 195— 208. 

Ariens EJ, Wuis EW, Veringa EJ. Stereoselectivity of bioactive xenobiotics a pre-Pasteur attitude in medicinal chemistry, pharmacokinetics and clinical pharmacology. Biochem Pharmacol 1988 37 9-18. 

Pharmacokinetics may also form the basis of a decision on the choice of compound from a series for development. It is not uncommon for a company to take three or four compounds of a series as far as the first study in man and to choose for development the compound that is most attractive from the pharmacokinetic point of view. Similarly, the development of achiral compounds rather than racemic mixtures is generally preferred and it may be necessary to establish whether stereoselective metabolism occurs in man and, if so, which enantiomer has the more desirable profile. 

Mamiya K, leiri I, Shimamoto J, Yukawa E, Imai J, Ni-nomiya H et al. The effects of genetic polymorphims of CYP2C9 and CYP2C19 on phenytoin metabohsm in Japanese adult patients with epilepsy studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998 29(12) 1317-23. 

Desta Z, Kivisto KT, Lilja JJ, et al. Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice. Br J Clin Pharmacol 2001 52(4) 399-407. 

The mean elimination half-life is about 6 h. The O-demethylation of tramadol to Ml, the main analgesic effective metabolite, is catalyzed by cytochrome P450 (CYP) 2D6, whereas A-demeth-ylation to M2 is catalyzed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and A-demethylation of tramadol as well as renal elimination are stereoselective.56... 

A.R. Mahasen, H.A. Heba, T.A. Bushra, YA.-E. Hassan, N. Kenichiro, Stereoselective HPLC assay of donepezil enantiomers with UV detection and its application to pharmacokinetics in rats, J. Chromatogr. B. 830 (2006) 114-119. 

Fukumoto, K., Kobayashi, T., Komamura, K., Kamakura, S., Kitakaze, M., and Ueno, K. 2005. Stereoselective effect of amiodarone on the pharmacokinetics of racemic carvedilol. Drug Metab. Pharmacokinet. 20 423-427. 

A number of factors must be considered in the area of stereoselectivity (31). Distinct differences are noted between stereoisomers in absorption/ uptake, activity at the target or receptor site, pathways and rate of bioconversion, and pharmacokinetics. All of these factors are applicable in the case of triadimefon and are examples of processes that may be manipulated to enhance disease control effectiveness. 

Eichelbaum M. Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem Pharmacol 1988 37 93-6. 

P. Le Corre, D. Gibassier, E Sado, and R. Le Verge, Stereoselective metabolism and pharmacokinetics of disopyramide enantiomers in humans. Drug Melab. Dispos., 16 858 (1988). 

There may be cases in which a stereochemically pure drug is found preferable on the basis of its stereoselective pharmacokinetics For example, even when enantiomers are equipotent, they may be different from one another in their pathways of elimination for instance, one enantiomer may depend on renal pathways, whereas the other is extensively metabolized. Hence in subjects with reduced renal function such as elderly patients, administration of the racemate may result in an excessive accumulation of one of the enantiomers. Consequently, the single enantiomer that does not depend on the kidneys for its elimination may prove beneficial as compared to the racemate. 

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