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H W Ruelius

Publications and source records attributed to H W Ruelius.

At least 19 recordsLinked to original sources
PubMed1987

Extrapolation from animals to man: predictions, pitfalls and perspectives.

Comparative drug disposition studies can be useful in extrapolating from animals to man provided that the criteria indicating interspecies similarity in disposition reflect similar exposure to the foreign compound. Interspecies variability, on the other hand, can often be related to physiological or biochemical differences, thereby providing a rationale for the unsuitability or limitations of a species as a model for human metabolism. Retrospective evaluation of the following examples illustrates the relevance of the indicated disposition characteristics to risk and efficacy assessment: (a) oxaprozin (route of excretion, enterohepatic circulation and exposure; plasma concentrations and efficacy prediction); (b) ciramadol (species differences in presystemic elimination and major metabolic pathway); (c) acebutolol (pharmacologically active human metabolite absent in one of the toxicology species); (d) esmolol (duration of pharmacologic effect controlled by species dependent nature of blood esterases). Stereochemical preferences in the disposition of racemic drugs often differ among species. Extrapolations from one species to another cannot be made in this situation. Pharmacokinetic parameters based on measurements of the sum of the isomers are meaningless and potentially misleading. Future improvements can come from: computer assisted predictions of metabolic pathways; increased use of human tissues; and use of animal species physiologically similar to humans, e.g. the miniature swine.

Acebutolol↗
PubMed1987

Interactions between oxaprozin glucuronide and human serum albumin.

1. The first step in the interaction between oxaprozin glucuronide and human serum albumin (HSA) is formation of a reversible complex which then leads to the following reactions; (a) acyl migration of the aglycone from position 1 to positions 2, 3 and 4 of the glucuronic acid moiety; (b) hydrolysis of the glycosidic bond; and (c) covalent binding of oxaprozin to the HSA molecule. The isomers of oxaprozin glucuronide formed in (a) and the covalently bonded drug in (c) are also hydrolyzed to oxaprozin. 2. Oxaprozin and ligands known to bind at Site II as classified by Sudlow et al. (1976), also called the benzodiazepine binding site (Müller and Wollert 1975), inhibit these reactions with oxaprozin glucuronide, while ligands which are known to bind at other sites on HSA do not. 3. Modification of a single tyrosine residue, located within Site II, with tetranitromethane, diisopropylfluorophosphate, and p-nitrophenylacetate causes significant reduction of the covalent binding of oxaprozin to HSA. 4. Tetranitromethane modification of HSA decreases all three reactions, while not inhibiting the formation of the reversible complex, indicating that the tyrosine located in Site II (tyr-411)acts as the nucleophile in these reactions. 5. Chemical modification of lysine residues has only a small effect on the reactions while modification of the lone free sulphhydryl (cys) in HSA has no effect.

Binding Sites↗
PubMed1986

Reactions of oxaprozin-1-O-acyl glucuronide in solutions of human plasma and albumin.

Hydrolysis and rearrangement (isomerization by acyl migration) of oxaprozin glucuronide are greatly accelerated by plasma and human serum albumin. Albumin accounts for all the hydrolytic activity in plasma and no esterase is involved. The isomeric esters formed by rearrangement are also good substrates for the hydrolysis reaction. Another reaction between oxaprozin glucuronide and albumin leads to covalent binding of the aglycone. Similar reactions leading to covalent binding have been described for other acyl glucuronides by several investigators. In the case of oxaprozin, there is little or no potential for biological significance of covalent binding because the reaction is almost entirely inhibited by low concentrations of the drug. All three reactions are pH dependent but not to the same extent. They can be considered to be transacylations to the hydroxyl ion (hydrolysis), to a different OH-group of the glucuronic acid moiety (rearrangement) or to a nucleophilic group on the albumin molecule (covalent binding). All three reactions are greatly inhibited by the same compounds suggesting a common reaction site. This site has certain features in common with the indole or benzodiazepine binding site of human serum albumin. A scheme is proposed in which the first step is reversible binding of the acyl glucuronide to this site in analogy to the known reversible binding of reactive esters (such as p-nitrophenyl acetate) to the same site. All three reactions are inhibited by compounds such as naproxen and decanoic acid which are known to also inhibit the acylation of albumin by reactive esters and the reversible binding of benzodiazepines.

Carbon Radioisotopes↗
PubMed1985

Protein binding of oxazepam and its glucuronide conjugates to human albumin.

The binding of oxazepam and its glucuronide conjugates to human serum albumin (HSA), as well as the binding interactions of the drug and its metabolites, were examined by equilibrium dialysis and kinetic probe studies. Oxazepam and its S(+) glucuronide are bound to the HSA molecule with affinity constants of 3.5 X 10(5) M-1 and 5.5 X 10(4) M-1, respectively, which were independent of protein concentration over a range of 0.1 to 5.0 g/dl. The R(-) glucuronide bound weakly to albumin, with the binding parameter, N X K, increasing at lower albumin concentrations. Pre-acetylation of fatty acid free-HSA resulted in decreased binding of all three compounds, probably by altering the conformation of the binding sites. Kinetic probe studies with p-nitrophenyl acetate indicate that oxazepam and its S(+) glucuronide shared a common binding site on HSA, but that the R(-) glucuronide bound at another site. Oxazepam binding was unaffected by the presence of its glucuronide conjugates but was inhibited by fatty acids. The percentage of oxazepam bound to plasma proteins in patients with renal impairment (94%) was lower than in normal volunteers (97%). This lower binding can neither be attributed to lower albumin concentrations because of the large binding capacity of the protein and linearity of N X K nor to displacement by elevated concentrations of glucuronide conjugates, but it may be ascribed partly to increased plasma fatty acids.

Glucuronates↗
PubMed1979

The disposition of [14C]iprindole in man, dog, miniature swine, rhesus monkey and rat.

1. Absorption of a single oral dose of [14C]iprindole was rapid in rats, rhesus monkeys, miniature swine, dogs and human volunteers. In all species except the rat, most of the radioactivity in the blood resided in the plasma. Small amounts of unchanged iprindole were detected in the plasma of rats and rhesus monkeys but not in man and miniature swine. 2. Radioactivity was excreted mainly in the urine of man, miniature swine and rhesus monkey, but in the faeces of rat and dog. 3. Urinary radioactivity was associated with basic (free and conjugated), acidic and highly polar, water soluble metabolites. At least 20 metabolites as well as small amounts of unchanged drug were detected in the basic fractions of each species' urine. 4. Many of these metabolites were common to all species; however, qualitative as well as quantitative differences were apparent. Mass-spectrometric analysis of several metabolites indicated N-demethylation and oxidation of the alicylic ring or a combination of both pathways.

Animals↗
PubMed1978

Comparative metabolism of lorazepam in man and four animal species.

The metabolic disposition of lorazepam (Wy-4036) in man, dog, cat, rat and miniature swine is compared. Except in the cat, absorption of lorazepam is rapid in these species. Absorption in humans is nearly complete. Lorazepam glucuronide is the major metabolite in all species except the rat in which a dihydrodiol derivative is the main product of lorazepam biotransformation. Lorazepam glucuronide, which has no demonstrable CNS activity, is also present in the plasma of all species investigated. The concentrations of lorazepam in rat brain correlate well with those in plasma but are about three times higher. The urinary route of excretion predominates in man, dog and miniature swine while in the rat the bulk of the drug-related material is eliminated with the feces as a consequence of biliary excretion.

Absorption↗
PubMed1977

Clinical pharmacokinetics of lorazepam. II. Intramuscular injection.

A single dose of 4 mg of lorazepam was injected into the deltoid muscles of six healthy male volunteers. Multiple venous blood samples were drawn during 48 hr after the dose and all urine was collected for 24 hr after the dose. Concentrations of lorazepam and its major metabolite, lorazepam glucuronide, were determined by electron-capture gas-liquid chromatography. Lorazepam was rapidly absorbed from the injection site, reaching peak concentrations within 3 hr. Mean pharmacokinetic pamrameters for unchanged lorazepam were: apparent absorption half-life: 21.2 min; elimination half-life: 13.6 hr; volume of distribution: 0.9 L/kg; total clearance: 58.2 ml/min. Lorazepam glucuronide rapidly appeared in plasma, reached peak concentrations within 12 hr of the dose, then was eliminated approximately in parallel with the parent drug. Within 24 hr a mean of 47.6% of the dose was recovered in the urine as lorazepam glucuronide and less than 0.5% was recovered as unchanged lorazepam.

Adult↗
PubMed1976

Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam.

Eight healthy male subjects received single 2-mg oral doses of lorazepam containing 24 muCi/mg of 2-14C-lorazepam. Multiple venous blood samples were drawn during the first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first-order half-life of 15 min. The peak plasma concentration was 16.9 ng/ml, measured in the pooled sample drawn 2 hr after the dose, This corresponded to the time at which clinical effects appeared to be maximal. The apparent elimination half-life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.

Administration, Oral↗
PubMed1976

Evaluation of a DNA polymerase-deficient mutant of E. coli for the rapid detection of carcinogens.

Differential growth inhibition of two E. coli cultures was evaluated as a rapid screening technique for chemical carcinogens. Of the carcinogens tested, only "direct acting" carcinogens produced positive results. Furthermore, this test is not a quantitative assay in that neither was a dose--response relationship seen nor did potent carcinogens necessarily show a greater response than weaker carcinogens.

Carcinogens↗