Probing the cytochrome P-450 2B1 active site with diamantoid compounds.

Hydrocarbone diamantane has been shown to be a specific substrate with a high affinity for the binding site of PB-inducible cytochrome P-450 2B1 (Hodek et al. 1988). Using a difference spectroscopy approach, a battery of diamantane analogues and diamantane oxygen containing derivatives were examined for their interaction with P-450 2B1 active site. Of the compounds (diamantane and its analogues, adamantane and triamantane) tested, diamantane had the lowest value of a spectral dissociation constant Ks = 0.5 mumol/l, indicating that diamantane was accommodated well to the cytochrome P-450 2B1, hence values of 0.46 nm and 0.66 nm for the width and length of the diamantane molecule, respectively, were used to describe of the dimensions the cytochrome P-450 binding site. Adamantane (Ks = 1.3 mumol/l) is relatively small and thus it binds loosely whereas triamantane (Ks = 4.3 mumol/l) is bulky enough to fit the binding site. This conclusion has been confirmed by spectral competition experiments as well as metabolic studies. Of all oxygen containing derivatives diamantane 1,6-dicarboxylic acid dimethylester only exhibited a pronounced ligand interaction with cytochrome P-450. Using molecular dimensions of this derivative the distance of 0.56 nm from the heme iron to the center of the substrate binding site was estimated.

Metabolism of diamantane by rat liver microsomal cytochromes P-450.

1. Diamantane binds to liver microsomes from phenobarbital-treated rats with an apparent Ks value of 5.2 x 10(-7) mol/l. This value being lower than that obtained for perhydrophenanthrene indicates that diamantane is very strongly bound to microsomal cytochrome P-450. 2. Metabolic studies show that liver microsomes from phenobarbital-treated rats readily metabolize diamantane to mono-, di- and possibly tri-hydroxy derivatives, whereas liver microsomes from beta-naphthoflavone-induced rats do not bind this hydrocarbon or metabolize it. 3. Reconstituted cytochromes P-450 b and e were more efficient in the hydroxylation of diamantane than liver microsomes; metabolites formed by the reconstituted system do not include all the products formed by microsomes, which indicates the involvement of forms of cytochrome P-450 other than the isozymes b and e.

[Circadian changes in the pharmacokinetics and effects of fenazepam in rats]. / Tsirkadnye izmeneniia v farmakokinetike i éffektakh fenazepama u krys.

It was established that phenazepam is excreted from the rat blood several times more rapidly when administered at night. In this case the minimal pharmacological effect is observed as to various actions. During the drug administration in the morning and evening hours the greatest effect is observed that correlates well with the maximal concentrations of the drug after its administration at this time.

[Clinical pharmacokinetics of azabutyron, a new short-term action neuroleptic]. / Klinicheskaia farmakokinetika azabutirona--novogo neiroleptika kratkovremennogo deistviia.

Pharmacokinetics of azabutyron--a new Soviet-made neuroleptic was studied clinically without anesthesia and also during surgery against the background of deep and surface fluorothan anesthesia in conjunction with artificial nitrous oxide and oxygen ventilation of the lungs (2:1). After intravenous administration of the drug in a dose of 4 mg/kg its maximum concentration (about 8 gamma/ml) was recorded in 5 minutes and the amount eliminated during 2 hours of observation comprised 1--2 per cent of the dose introduced. In practically healthy individuals with no anesthesia the pharmacokinetics of azabutyron lies within the limits of a bicompartment pharmacokinetics model, while surface anesthesia, blood loss changes the pharmacokinetics of the drug to such an extent that is has to be described from the standpoint of the unicompartment model system.