Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period.

The phosphodiesterase 5 inhibitor sildenafil is a potential therapeutic option in the treatment of persistent pulmonary hypertension of the newborn (PPHN) and neonatal hypoxemia. In this open-label trial, 36 term neonates with PPHN or hypoxemia were administered intravenous sildenafil for up to 7 days starting within 72 h of birth. A mixed-effects pharmacokinetic model that included two-compartment disposition of sildenafil and its metabolite and an effect of postnatal age on sildenafil clearance was used to describe plasma concentration-time data of parent and metabolite. Allometrically scaled sildenafil clearance increased threefold from the first day after birth to values similar to those in adults by the first week. Volume of distribution of sildenafil in neonates was fourfold higher than in adults, resulting in a longer terminal half-life in neonates (48-56 h) compared to adults. Increase in sildenafil clearance in the early postnatal period likely reflects maturation of CYP-mediated N-demethylation.

Pharmacokinetics and pharmacodynamics of sibrafiban alone or in combination with ticlopidine and aspirin.

AIMS: The purpose of this clinical study was to evaluate the effects of a ticlopidine/aspirin combination on the pharmacokinetics and pharmacodynamics of sibrafiban and the tolerability of the combination therapy METHODS: Thirty-eight healthy male volunteers were randomized to receive one of the following treatments for 7 days: sibrafiban (n = 12), ticlopidine/aspirin (n = 12), or the combination treatment sibrafiban/ticlopidine/aspirin (n = 14). Concentrations of the active metabolite of sibrafiban, Ro 44-3888, in plasma and urine were determined by column-switching liquid chromatography combined with tandem mass spectrometry. The pharmacodynamics of sibrafiban and ticlopidine/aspirin were examined by measuring the inhibition of ADP- or collagen-induced platelet aggregation. RESULTS: The addition of ticlopidine/aspirin to sibrafiban did not significantly alter the pharmacokinetic parameters of Ro 44-3888. the geometric mean ratio for AUC(0,12h) was 110 (95% CI 0.82, 1.22). Separately, sibrafiban and ticlopidine/aspirin inhibited ADP-and collagen-induced platelet aggregation and the effects of the two treatments were additive. For example, the average inhibition of ADP-induced platelet aggregation over 12 h was 42% in the sibrafiban treated group, 55% in the ticlopidine/aspirin group and 69% in the sibrafiban/ticlopidine group. The bleeding time was prolonged in the treatments with ticlopidine/aspirin (8.1 min) and sibrafiban/ticlopidine/aspirin (8. 6 min) compared with sibrafiban alone (3.5 min). CONCLUSIONS: This study shows a significant pharmacodynamic interaction between sibrafiban and ticlopidine/aspirin. Consequently, the simultaneous administration of sibrafiban and ticlopidine/aspirin should be carefully monitored to ensure the patient's coverage with an antiplatelet drug without exposure to an excessive bleeding risk.

Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers.

AIMS: This study constituted the first administration of the oral platelet inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44-3888, the active principle of sibrafiban, after single ascending oral doses of sibrafiban. Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44-3888. METHODS: The study consisted of three parts. Part I was an open ascending-dose study to determine target effect ranges of sibrafiban. Part II, a double-blind, placebo-controlled, parallel-group study, addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect. Part III was a double-blind, placebo-controlled, ascending-dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban. RESULTS: At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free Ro 44-3888 in plasma were linear whereas those of total Ro 44-3888 were non-linear because of the saturable binding to the glycoprotein IIb-IIIa receptor. Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of 15.9 ng ml-1. At sibrafiban doses up to 2 mg, ADP-induced platelet aggregation was inhibited by 50%, whereas the inhibition of TRAP-induced platelet aggregation was about 20-30%. At the higher doses, ADP-induced platelet aggregation was almost completely inhibited while a clear dose-response could be observed with TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg. Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban (5-7 min, >30 min in one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose escalation (prolongation of the Ivy bleeding time >30 min in three out of four subjects per dose group) was reached. The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC and AUE) were below 20%, thus lying well within the pre-set level of acceptance. CONCLUSIONS: With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations, Ro 44-3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of arterial thrombosis in patients with acute coronary syndrome.

Pharmacokinetics of cefetamet in plasma and skin blister fluid.

Cefetamet pivoxil is an oral cephalosporin with enhanced affinity for the target penicillin-binding proteins 1 and 3 and an increased stability to beta-lactamases compared with older cephalosporins, such as cefalexin or cefaclor. The pharmacokinetics of cefetamet pivoxil was determined after the seventh and final dose of 500 mg of cefetamet pivoxil in eight healthy volunteers. Concentrations in plasma and cantharidin-induced skin blister fluid were determined by a high-performance liquid chromatography method. In addition, protein binding was assessed. Cmax was 4.8 +/- 1.7 micrograms/ml in skin blister fluid and 5.1 +/- 2.1 micrograms/ml in plasma. Tmax was delayed in skin blister fluid compared with plasma (3.9 +/- 1 versus 2.8 +/- 0.8 h; P < 0.001), and t1/2 was longer in skin blister fluid than in plasma (3.1 +/- 0.5 versus 2.3 +/- 0.3; P < 0.005). The mean percent penetration into cantharide blister fluid was 129% +/- 24% when measured as total drug and 149% +/- 28% when measured as free drug (P < 0.001). These data suggest that cefetamet has an excellent penetration into inflammatory interstitial fluid.

Interaction of some beta-receptor blockers with the transport system of glucose in human erythrocytes.

The influence of 15 of the most frequently used beta-receptor blockers on the glucose transport in human erythrocytes was investigated. It was found out that 10 compounds have no effect on the glucose transport and that their lipophilicities are very low. The inhibition constants and the inhibition kinetics of the glucose uptake of the other 5 beta-receptor blockers were estimated. No correlation exists between their affinities to the glucose transport sites and the partition coefficients.

The affinities of benzodiazepines to the transport protein of glucose in human erythrocytes.

By kinetic analysis we estimated that all the 16 benzodiazepines investigated are inhibitors of the glucose uptake in human erythrocytes; their affinities, however, differ remarkably. The individual KI values ranged over 2 orders, the partition coefficients in a mixture of octanol/water over 3 orders of magnitude. Thus, the lipophilities of the benzodiazepines differ considerably; they don't agree with the trend of the KI values with exception of structurally very similar preparations. The thermodynamic parameters delta F degree, delta H degree and delta S degree for the association of the benzodiazepines to the transport protein were mostly of negative sign. From the results we discussed the importance of the chemical groupings for the inhibitory effect of the benzodiazepines on the glucose uptake as well as the mode of interaction between the benzodiazepines and the transport protein. Some parallels between the affinities of the benzodiazepines to the transport protein, to the serum albumin and to the receptors of the central nervous system were considered.

The competitive inhibition of glucose transport in human erythrocytes by compounds of different structures.

By kinetic analysis we found that the transport protein for glucose in human erythrocyte membranes has different binding sites for competitive inhibitors. They all change the transport protein with the effect that it loses its affinity to glucose. Some of the competitive inhibitors alter the conformation of the transport protein, so that other ones cannot be bound. There are inhibitors, however, which do not affect the affinity of other competitive inhibitors. A schematic model of our assumption about the mechanism of the competitive inhibition of glucose transport is presented.

Antisickling agents as inhibitors of glucose transport in human erythrocytes.

It was found that 2-amino-3-indolepropionic acid (tryptophan) and 2-amino-3-phenylpropionic acid (phenylalanine) benzylesters, compounds which inhibit cell sickling, are inhibitors of glucose transport in normal human erythrocytes. The mechanism underlying both processes is discussed.

Inhibition kinetics of enzymatic and membrane transport processes with two inhibitor molecules.

The kinetics of the enzymatic and transport processes is described for cases in which not only one but also two inhibitor molecules can interact with one protein molecule. A method is stated to determine the different dissociation constants for the mixed, competitive and noncompetitive inhibition.

Interaction of chlorpromazine with the transport system of glucose in human erythrocytes.

The characteristics of inhibition of the glucose uptake in human erythrocytes by chlorpromazine (CPZ) was investigated. It was found that CPZ is a strong inhibitor. The inhibition kinetics indicates that also two molecules of CPZ can bind to the transport system and so from two different CPZ-complexes. The dissociation constants of both the CPZ-complexes and the pH- and temperature-dependence of the inhibition were estimated.

The effect of homologous local anesthetics of the 4-alkoxy- and 4-alkylamino-benzoic acid-diethylamino-esthylester- hydrochloride series on the glucose transport in human erythrocytes.

The homologous compounds of the 4-alkoxy- and 4-alkylamino-series inhibit the exchange transport of glucose in human erythrocytes; they show a competitive inhibition with one or two inhibitor molecules which become bound to a singular site of the transport system for glucose. The importance of length of hydrocarbon chain of the localanesthetics for the mode of their action is discussed.

Diethylpyrocarbonate interferes with lipid-protein interaction and glucose transport in the human red cell membrane.

Diethylpyrocarbonate largely diminished both discontinuities in red cell glucose transport and also in red cell membrane ANS fluorescence at about 17--20 degrees C.

Interaction of DL-, D- and L-propranolol with the transport system of glucose in human erythrocytes.

The effect of D-, L- and DL-propranolol on the glucose uptake in human erythrocytes was studied. It was observed that all three compounds competitively inhibit the glucose transport and have identical inhibition constants. The pH dependence of the inhibition constant indicates that uncharged propranolol is a more potent inhibitor than the charged one. The thermodynamic parameters of the interaction of propranolol with the glucose transport system were determined and discussed.

Inhibition of glucose transport in human erythrocytes by benzylalcohol.

The inhibition of glucose transport by the non-ionizable local-anesthetic denzylalcohol is of the mixed type and independent of pH. The affinity of benzylalcohol to the free carrier is about three times larger than that to the carrier-glucose complex.

Interaction of local anesthetics with the transport system of glucose in human erythrocytes.

Local anesthetics inhibit the exhange transport of glucose in human erythroytes. All compounds tested showed a competitive inhibition except lidocaine and baycaine causing a non-competitive one. Moreover the transport system can bind two inhibitor molecules to one transport site as described for tetracaine and oxybuprocaine.

The pH and temperature dependence of the interaction of steroid hormones with the transport system of glucose in human erythrocytes.

The thermodynamic parameters deltaH degrees, deltaF degrees, deltaS degrees and the pH dependence of the interaction between steroids and the glucose carrier in human erythrocytes have been studied. The results indicate that, according to the structure of the steroids, hydrophilic as well as hydrophobic bonds can be involved in the association. For the binding of the C-21-steroids to the carrier the polarity rule has been observed to be valid. On the basis of the thermodynamic parameters it has been found that in the association process of the steroids with the carrier, simultaneous randomization of ordered water molecules is important.

Interaction of steroids with the transport system of glucose in human erythrocytes.

Steroids inhibit the exchange transport of glucose in human erythrocytes. The extent of inhibition is roughly correlated to the affinity of the steroids to the membrane lipids. All C-21-steroids tested show a competitive inhibition while the C-19-steriods show different types of inhibition. 5Beta-androstane-3,17-dione acts as a competitive inhibitor. The inhibition by testosterone is of mixed type, while with androst-4-ene-3,17-dione and 5alpha-androstane-3,17-dione a non-competitive inhibition is observed. In this case two inhibitor molecules can be bound per transport molecule. The "non-competitive" inhibitors compete also to some extent with the glucose binding. This effect, however, is at high inhibitor concentrations masked by the more powerful non-competitive inhibition. Competitive and non-competitive inhibitors compete with each other. The structural requirements for the different types of inhibition are discussed.