Svein Øie

Opiate antagonist receptor binding in vivo: evidence for a new receptor binding model.

The in vivo accumulation and retention of the opiate antagonist tracers [3H]diprenorphine and [3H]naloxone at cerebral opiate receptor sites in rats exceed that expected from their known in vitro receptor affinities. The [3H]diprenorphine serum and brain levels can be stimulated with a pharmacokinetic model that contains the receptors in a micro-compartment. The receptor micro-compartment consists of a population of binding sites next to a diffusion boundary which restricts ligand diffusion away from the receptor. Such an arrangement introduces a delay in the binding equilibrium of potent antagonists with the receptor sites and an increase in the apparent in vivo receptor affinity at subsaturating doses of the ligand; at saturating ligand concentrations these functions of the receptor micro-compartment are abolished. A physiological interpretation of the receptor micro-compartment could be the location of clustered opiate receptor sites on the exterior cell surface next to the synaptic cleft as the diffusion boundary. This kinetic approach involving a combination of pharmacokinetics and drug-receptor interactions permits the quantitative analysis of receptor site availability in the intact animal. Our results support the hypothesis that only one receptor population affects the in vivo disposition of the antagonist tracers, while they do not exclude the presence of low affinity binding sites that have been observed with the use of [3H]naloxone in vitro. Moreover, the binding site population observed in vivo may be responsible for mediating opiate agonist analgesia.

Effect of saturable binding on the pharmacokinetics of drugs: a simulation

The time‐courses of both total and unbound drug concentrations with time were simulated under conditions of saturable binding to either plasma proteins or tissues, or both, following a single intravenous dose. The curves were either linear, convex, or concave, depending upon the extent of distribution and the intrinsic ability of an eliminating organ to remove drug from the body. Saturable binding should therefore be considered whenever data showing nonlinear semilogarithmic decline are to be interpreted.

Drug Distribution and Binding

The distribution of drugs in the body depends on their lipophilicity and protein binding. Low plasma binding or high tissue binding or high lipophilicity usually means an extensive tissue distribution. In pharmacokinetics, the distribution is described by the parameter V, the apparent volume of distribution. This parameter measures the relative distribution of drugs between tissue and plasma and depends on the plasma and tissue binding and the lipophilicity of the drug. If the distribution of drug throughout the body is slow, V in the terminal phase will also depend on the clearance of the drug. At equilibrium, V will theoretically not be lower than 7 L in a 70‐kg person, but it has no upper limit. The extent to which a drug distributes affects the half‐life of the drug and the fluctuation of the concentration at steady state on multiple dosing, but not the average steady‐state concentration.

Use of the intestinal bile acid transporter for the uptake of cholic acid conjugates with HIV-1 protease inhibitory activity.

AbstractPurpose. To investigate the ability of the human intestinal bile acid transporter to transport cholic acid conjugates with potential HIV-1 protease inhibitory activity. Methods. Cholic acid was conjugated at the 24 position of the sterol nucleus with various amino acids and amino acid analogs. The CaCo-2 cell line was used as a model to investigate the interaction of these bile acid conjugates with the human intestinal bile acid transporter. Interaction between the carrier and the conjugates was quantified by inhibition of taurocholic acid transport and confirmed by transport of radiolabelled conjugates in this cell line. Results. The highest interaction with the transporter, as quantified by inhibition of taurocholic acid transport, occurred when a single negative charge was present around the 24 to 29 region of the sterol nucleus. A second negative charge or a positive charge significantly reduced the interaction. Transport of radiolabelled cholyl-L-Lys-ε-tBOC ester and cholyl-D-Asp-β-benzyl ester was inhibited by taurocholic acid. Of all tested compounds, only cholyl-D-Asp-β-benzyl ester showed modest HIV-1 protease inhibitory activity with an IC50 of 125 μM. Conclusions. Cholic acid-amino acid conjugates with appropriate stereochemistry are recognized and transported by the human bile acid transporter and show modest HIV- 1 protease inhibitory activity. Transport of these conjugates by the bile acid carrier is influenced by charge and hydrophobicity around the 24 position of the sterol nucleus.

MOLECULAR MODELING OF THE INTESTINAL BILE ACID CARRIER : A COMPARATIVE MOLECULAR FIELD ANALYSIS STUDY

A structure–binding activity relationship for the intestinal bile acidtransporter has been developed using data from a series of bile acid analogsin a comparative molecular field analysis (CoMFA). The studied compoundsconsisted of a series of bile acid–peptide conjugates, withmodifications at the 24 position of the cholic acid sterol nucleus, andcompounds with slight modifications at the 3, 7, and 12 positions. For theCoMFA study, these compounds were divided into a training set and a test set,comprising 25 and 5 molecules, respectively. The best three-dimensionalquantitative structure–activity relationship model found rationalizesthe steric and electrostatic factors which modulate affinity to the bile acidcarrier with a cross-validated, conventional and predictive r2of 0.63, 0.96, and 0.69, respectively, indicating a good predictive model forcarrier affinity. Binding is facilitated by positioning an electronegativemoiety at the 24–27 position, and also by steric bulk at the end of theside chain. The model suggests substitutions at positions 3, 7, 12, and 24that could lead to new substrates with reasonable affinity for the carrier.

Use of the intestinal and hepatic bile acid transporters for drug delivery

Abstract There are several possible approaches that can be used to increase the oral absorption of drugs. Recently, utilization of carrier-mediated transport mechanisms in the intestinal tract to increase the bioavailability of drugs has drawn a great deal of attention. This review describes the potential use of this approach, using the bile acid carrier system in both the intestinal tract and the liver. The physiology, ontogeny and molecular biology of the ileal and hepatic transporters are described and an overview is presented of the compounds that are transported by these carriers. Furthermore, the structural requirements for recognition by these carrier systems is presented and the current utilization of this mechanism is reviewed. The importance of carrier-mediated bile acid transport in drug delivery is addressed.

Factors responsible for interindividual differences in the dose requirement of phenprocoumon

SummaryThe total and unbound plasma concentrations of phenprocoumon and the prothrombin complex activity were determined in 51 patients on phenprocoumon.A 7-fold difference in the dosing rate (10–70 µg/kg/day) was required to maintain the prothrombin complex activity at 11–30% of normal. The variation in dosing requirement was mainly due to inter-individual differences in the intrinsic clearance of phenprocoumon and only to a minor degree to differences in sensitivity to it.On average patients with myocardial infarction required only 2/3 of the daily dose of phenprocoumon of post cardiac surgery patients and patients with thrombosis and emboli. That difference appeared to be due to higher clearance in surgical patients and to greater resistance to phenprocoumon in patients with thrombosis and emboli. The total clearance in patients varied approximately 5-fold. It was better predicted by the interindividual intrinsic clearance (r=0.84) than by the unbound fraction (r=0.15).

Does α1-Acid Glycoprotein Act as a Non-functional Receptor for α1-Adrenergic Antagonists?

Abstract— The ability of a variety of α1‐acid glycoproteins (AAG) to affect the intrinsic activity of the α1, ‐adrenergic antagonist prazosin was studied in rabbit aortic strip preparations. From these studies, the activity of AAG appears to be linked to their ability to bind the antagonist. However, a capability to bind prazosin was not the only requirement for this effect. The removal of sialic acid and partial removal of the galactose and mannose residues by periodate oxidation of human AAG all but eliminated the ability of AAG to affect the intrinsic pharmacologic activity of prazosin, although the binding of prazosin was not significantly affected. The presence of bovine AAG, a protein that has a low ability to bind prazosin, reduced the effect of human AAG on prazosin activity. Based upon these results, we propose that AAG is able to bind in the vicinity of the α1‐adrenoceptors, therefore extending the binding region for antagonists in such a way as to decrease the ability of the antagonist to interact with the receptor. The carbohydrate side‐chains are important for the binding of AAG in the region of the adrenoceptor.

Disposition of vitamin K1 after intravenous and oral administration to subjects on phenprocoumon therapy

Abstract The disposition and prothrombin-complex activity of a new i.v. dosage form of vitamin K 1 using mixed micelles of glycocholic acid and lecithin as a vitamin K 1 solution was studied in 9 volunteers on an oral phenprocoumon dosage regimen. Each of two volunteers received 10, 20, 40 or 60 mg i.v. and oral doses in a cross-over fashion. An additional subject received a single 60 mg i.v. bolus dose. The intravenous doses were well tolerated with no subjective or objective side-effects. Using a sensitive gas chromatographic assay (detection limit ≈ 5 ng/ml), the concentrations of vitamin K 1 could be followed for 24–36 h after the i.v. doses and for 12–33 h after the oral dose. The steady-state apparent volume of distribution was 20±6 liters and the clearance was 70±19 ml/min. The bioavailability demonstrated large inter-individual variation ranging from 3.5% to 60%. After the i.v. dose, vitamin K 1 showed multi-compartmental characteristics with a terminal half-life of 14±6 h. No dose dependency was detected in any of the pharmacokinetic parameters. The pharmacologic activity of vitamin K 1 after i.v. and oral dosing, defined as the area under the curve of the increase in the prothrombin-complex activity over baseline values during phenprocoumon therapy, correlated well with the logarithmic value of the area under the plasma concentration-time of vitamin K 1 ( r 2 = 0.677, t = 5.42, P

Sequential First‐Pass Metabolism of Nortilidine: The Active Metabolite of the Synthetic Opioid Drug Tilidine

The disposition of nortildine, the active metabolite of the synthetic opioid drug tilidine, was investigated in healthy volunteers in a randomized, single‐dose, three‐way crossover design. Three different treatments were administered: tilidine 50 mg intravenously, tilidine 50 mg orally, and nortilidine 10 mg intravenously. The plasma concentrations of tilidine, nortilidine, and bisnortilidine were determined and subjected to pharmacokinetic analysis using noncompartmental methods. The systemic bioavailability of tilidine was low (7.6% ± 5.3%) due to a pronounced first‐pass metabolism. The areas under the plasma concentration versus time curves (AUC) of nortilidine were similar following either oral or intravenous administration of tilidine 50 mg (375 ± 184 vs. 364 ± 124 ng•h•ml−1). AUC of nortilidine was 229 ± 42 ng•h•ml−1 after IV infusion of nortilidine 10 mg and thus much greater than after IV tilidine corrected for differences in dose. Nortilidine had a much lower volume of distribution (275 ± 79 vs. 1326 ± 477 L) and a somewhat lower clearance (749 ± 119 vs. 1198 ± 228 ml/min) than tilidine. About two‐thirds of the dose of tilidine was metabolized to nortilidine, although only half of the latter fraction was available in the peripheral circulation. Nortilidine was subsequently metabolized to bisnortilidine. The mean ratio of the AUC of bisnortilidine to nortilidine was 0.65 ± 0.14 following IV administration of nortilidine but 1.69 ± 0.38 and 1.40 ± 0.27 following oral and intravenous administration of tilidine, respectively. The shapes of the plasma concentration‐time curves of the metabolites and parent drug declined in parallel, indicating that the disposition of the metabolites is formation rate limited. Thus, although two‐thirds of the dose of tilidine is metabolized to nortilidine, only one‐third of the dose is available systemically as nortilidine for interaction with the opiate receptors after both intravenous and oral dosing of tilidine. The remaining part of nortilidine is retained in the liver and is subsequently metabolized to bisnortilidine and yet unknown compounds.