Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Structural elements of the gamma-aminobutyric acid type A receptor conferring subtype selectivity for benzodiazepine site ligands. Prevalence between different alpha subunits performing the benzodiazepine binding sites in native heterologous GABA(A) receptors containing the alpha2 subunit. Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. Ambien online references

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Drug Metab Dispos. 2001 Oct;29(10):1316-24.
Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.

Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.

Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Kashima, Yodogawa-ku, Osaka, Japan. yoichi_naritomi

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po.fujisawa.co.jp

We investigated the quantitative prediction of human hepatic metabolic clearance from in vitro experiments focusing on cytochrome P450 metabolism with eight model compounds, FK1052, FK480, zolpidem, omeprazole, nicardipine, nilvadipine, diazepam, and diltiazem. For the compounds, in vivo human hepatic extraction ratios ranged widely from 0.03 to 0.87. In vitro and in vivo hepatic intrinsic clearance (CL(int)) values for each compound were measured and calculated in rats and/or dogs and humans. CL(int,in vitro) was determined from a substrate disappearance rate at 1 microM in hepatic microsomes, which was a useful method. CL(int,in vivo) was calculated from in vivo pharmacokinetic data using three frequent mathematical models (the well stirred, parallel-tube, and dispersion models). The human scaling factor values (CL(int,in vivo)/CL(int,in vitro)) showed marked difference among the model compounds (0.3-26.6-fold). On the other hand, most of the animal scaling factors were within 2-fold of the values in humans, suggesting that scaling factor values were similar in the different animal species. When human CL(int,in vitro) values were compared with the actual CL(int,in vivo), correlation was not necessarily good. By contrast, using human CL(int,in vitro) corrected with the rat and/or dog scaling factors yielded better predictions of CL(int,in vivo) that were mostly within 2-fold of the actual values. Furthermore, successful predictions of human CL(oral) and hepatic extraction ratio (E(H)) were obtained by use of the human CL(int,in vitro) corrected with animal scaling factors. The new variant method is a simple one, incorporating additional information from animal studies and providing a more reliable prediction of human hepatic clearance.

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J Biol Chem. 1999 May 7;274(19):13370-4.
Structural elements of the gamma-aminobutyric acid type A receptor conferring subtype selectivity for benzodiazepine site ligands.

Renard S, Olivier A, Granger P, Avenet P, Graham D, Sevrin M, George P, Besnard F.

Department of Genomic Biology, Synthelabo, 10 rue des Carrieres, 92500 Rueil-Malmaison, France.

gamma-aminobutyric acid type A (GABAA) receptors comprise a subfamily of ligand-gated ion channels whose activity can be modulated by ligands acting at the benzodiazepine binding site on the receptor. The benzodiazepine binding site was characterized using a site-directed mutagenesis strategy in which amino acids of the alpha5 subunit were substituted by their corresponding alpha1 residues. Given the high affinity and selectivity of alpha1-containing compared with alpha5-containing GABAA receptors for zolpidem, mutated alpha5 subunits were co-expressed with beta2 and gamma2 subunits, and the affinity of recombinant receptors for zolpidem was measured. One alpha5 mutant (bearing P162T, E200G, and T204S) exhibited properties similar to that of the alpha1 subunit, notably high affinity zolpidem binding and potentiation by zolpidem of GABA-induced chloride current. Two of these mutations, alpha5P162T and alpha5E200G, might alter binding pocket conformation, whereas alpha5T204S probably permits formation of a hydrogen bond with a proton acceptor in zolpidem. These three amino acid substitutions also influenced receptor affinity for CL218872. Our data thus suggest that corresponding amino acids of the alpha1 subunit, particularly alpha1-Ser204, are the crucial residues influencing ligand selectivity at the binding pocket of alpha1-containing receptors, and a model of this binding pocket is presented.

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J Neurochem. 2001 Oct;79(1):183-91.
Prevalence between different alpha subunits performing the benzodiazepine binding sites in native heterologous GABA(A) receptors containing the alpha2 subunit.

del Rio JC, Araujo F, Ramos B, Ruano D, Vitorica J.

Department of Bioquimica, Bromatologia y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain.

The presence of two heterologous alpha subunits and a single benzodiazepine binding site in the GABA(A) receptor implicates the existence of pharmacologically active and inactive alpha subunits. This fact raises the question of whether a particular alpha subtype could predominate performing the benzodiazepine binding site. The hippocampal formation expresses high levels of alpha subunits with different benzodiazepine binding properties (alpha1, alpha2 and alpha5). Thus, we first demonstrated the existence of alpha2-alpha1 (36.3 +/- 5.2% of the alpha2 population) and alpha2-alpha5 (20.2 +/- 2.1%) heterologous receptors. A similar alpha2-alpha1 association was observed in cortex. This association allows the direct comparison of the pharmacological properties of heterologous native GABA(A) receptors containing a common (alpha2) and a different (alpha1 or alpha5) alpha subunit. The alpha2 subunit pharmacologically prevailed over the alpha1 subunit in both cortex and hippocampus (there was an absence of high-affinity binding sites for Cl218,872, zolpidem and [3H]zolpidem). This prevalence was directly probed by zolpidem displacement experiments in alpha2-alpha1 double immunopurified receptors (K(i) = 295 +/- 56 nM and 200 +/- 8 nM in hippocampus and cortex, respectively). On the contrary, the alpha5 subunit pharmacologically prevailed over the alpha2 subunit (low- and high-affinity binding sites for zolpidem and [3H]L-655,708, respectively). This prevalence was probed in alpha2-alpha5 double immunopurified receptors. Zolpidem displayed a single low-affinity binding site (K(i) = 1.73 +/- 0.54 microM). These results demonstrated the existence of a differential dominance between the different alpha subunits performing the benzodiazepine binding sites in the native GABA(A) receptors.

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J Pharmacol Exp Ther. 2001 Nov;299(2):793-800.
Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation.

Berson A, Descatoire V, Sutton A, Fau D, Maulny B, Vadrot N, Feldmann G, Berthon B, Tordjmann T, Pessayre D.

INSERM unit 481 and Centre Claude Bernard de Recherches sur les Hepatites Virales, Hopital Beaujon, Clichy, France. u481

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