A platform immunoassay for the quantification of biotherapeutics with glycine-serine linkers.

Assessing the pharmacokinetics of biotherapeutics is essential across all phases of drug development to understand drug exposure. At early stages, platform drug quantification immunoassays offer a versatile method for evaluating exposure for diverse biotherapeutics when specific reagents are not yet available, providing fast data for molecules with common structural features. To ensure clearly defined bioanalytical data, it is essential to conduct interference testing for anti-drug antibodies (ADA) or soluble target (starget), although these assays measure total exposure.

Comparison of assay formats used for the detection of pre-existing anti-drug antibodies against monoclonal antibodies.

Assessment of pre-existing anti-drug antibody (preADA) reactivity at early drug development stages can be beneficial for candidate selection. We investigated the applicability of a generic immune-complex anti-drug antibody (ADA) assay for early preADA assessment as an easily available alternative to the commonly used ADA bridging assay. The results confirmed the expected assay difference regarding isotype detectability.

Evaluation of potential biotin interference in immunogenicity testing.

One-step bridging assays typically used for immunogenicity testing may be challenged by biotin interference (BI) caused by widely available dietary supplementation or medically prescribed high-dose therapies. We investigated BI in two one-step antidrug antibody assays. Both assays showed biotin-related interference, with the peptide-based assay being less affected than the antibody-based assay.

Pharmacokinetics and metabolism of formestane in breast cancer patients.

Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.

Characterization of a novel diclofenac metabolite in human urine by capillary gas chromatography-negative chemical ionization mass spectrometry.

A sensitive analytical method was developed to characterize diclofenac metabolites in small amounts of body fluids. Desalted and lyophilized urine samples were extracted with supercritical carbon dioxide directly or after acidic hydrolysis. The extracts were derivatized with N-tert.

The disposition of [14C]-labelled benazepril HCl in normal adult volunteers after single and repeated oral dose.

1. The disposition of [14C]-labelled benazepril HCl, an ACE-inhibitor, was studied in four normal adult volunteers after a single oral dose of 20 mg and after repeated doses of 20 mg once daily for 5 days. Radioactivity was measured in plasma, urine and faeces.

Metabolic characteristics of oxcarbazepine (®trileptal) and their beneficial implications for enzyme induction and drug interactions.

Hepatic oxygenases of the cytochrome P-450 family play a major role in the clearance of various anti-epileptic drugs. These enzymes are susceptible both to induction and to inhibition. Phenytoin, carbamazepine (CBZ), primidone, and phenobarbitone, for instance, are potent enzyme inducers.

A new metabolite of diclofenac sodium in human plasma.

1. Among the phenolic metabolites of diclofenac in human plasma, an unknown compound (metabolite VI) was detected by h.p.

Single-dose kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine.

The kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide (CBZ-E) were studied in healthy subjects. A single oral dose of 100 mg of CBZ-E was given to eight subjects. Four of them were also given a single oral dose of 200 mg of CBZ-E.

Tricyclic drugs: potent mutagenicity of traces of a nitroarene formed in the reaction of opipramol with nitrite.

The tricyclic psychotropic drug opipramol (Insidon) reacts in vitro with sodium nitrite in acidic solution to form products including mutagens for Salmonella typhimurium TA98 and TA100. Two aspects are particularly noteworthy. The strong mutagenicity of the crude reaction mixture is almost exclusively due to a compound which is present only in trace quantities (less than 0.

The metabolism of 14C-oxcarbazepine in man.

The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.

Biotransformation of oxaprotiline: isolation and identification of metabolites in urine of rat and dog.

The biotransformation of oxaprotiline has been investigated in rat and dog after oral administration of racemic 14C-labelled oxaprotiline X HCl. Rats excreted 28% dose in urine within 120 h and dogs 32% within 96 h. The metabolites were isolated by liquid chromatography and their structures elucidated by spectroscopic methods.

The disposition and metabolism of 14C-oxprenolol.HCl in man.

The disposition and metabolism of oxprenolol have been investigated in two healthy male volunteers, following a single 160 mg oral dose of racemic 14C-labelled oxprenolol. Absorption was rapid and complete. Peak blood concentrations of total radioactivity were 8.

Isolation and stereospecific determination of the enantiomers of oxindazac by direct liquid chromatographic resolution on triacetylcellulose.

The preparation of the optically pure enantiomers of the antiphlogistic trial drug oxindazac via liquid chromatographic resolution of the corresponding tert.-butyl or benzyl ester on triacetylcellulose is described. Cleavage of the optically pure enantiomeric esters to the acids proceeds without significant racemization.

Indoxyl derivatives of drug metabolites.

Indoxyl derivatives were detected as minor products among the urinary metabolites of two trial drugs, a benzodiazepine (GP 55 129) and a benzophenone (CGP 11 952). Their structures were elucidated by NMR and mass spectroscopy. Presumably, metabolites containing potential aldehyde functions react spontaneously with endogenous indoxyl.

Disposition and pharmacokinetics of cadralazine and individual metabolites in man.

The absorption, biotransformation and elimination of the antihypertensive drug cadralazine, 2-(3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl)-ethylcarbazate , have been studied in two healthy male volunteers, following single 20 mg oral doses of the 14C-labelled preparation. Absorption was rapid and complete. In plasma total 14C-compounds reached maximum levels of 395 and 312 ng/g after 0.

The metabolic fate of 14C-oxaprotiline X HCl in man. III. Stereospecific disposition.

The disposition of the enantiomers of oxaprotiline has been investigated after single 100 mg oral doses of racemic 14C-labelled oxaprotiline X HCl in two healthy subjects. Absorption was complete. Peak blood concentrations of total 14C were 804 and 1010 ng equiv.

The metabolic fate of [14C]oxaprotiline.HCl in man. II. Isolation and identification of metabolites.

The new antidepressant agent oxaprotiline is extensively metabolized by man. Following an oral 50 mg dose of racemic [14C]oxaprotiline, most of the 14C was excreted in the urine as metabolites (greater than 98% total 14C); only 1% was excreted unchanged. Glucuronidation at the carbinol group of the molecule is the major metabolic pathway (83%).

The metabolic fate of [14C]oxaprotiline.HCl in man. I. Disposition and preliminary pharmacokinetics.

Absorption, biotransformation and elimination of [14C]oxaprotiline.HCl have been studied after oral administration of 50 mg doses to two human subjects. Absorption was complete, and peak blood concn.

Multiple inverse isotope dilution assay for cadralazine and four metabolites in biological fluids.

An inverse isotope dilution assay was developed for the specific determination of 14C-labelled cadralazine and four of its metabolites in biological samples. After addition of unlabelled carrier substances to the sample, metabolite IV was derivatized. The derivative and the unaltered compounds (I, II, III, V) were extracted and separated by high-performance liquid chromatography on silica gel.

Multiple inverse isotope dilution assay for the stereospecific determination of R(+)- and S(-)-oxprenolol in biological fluids.

An isotope dilution assay has been developed for the determination of both oxprenolol enantiomers in biological samples after administration of the racemic 14C-labelled mixture. The enantiomers were reacted with optically pure S(-)-1-phenylethyl isocyanate and the diastereoisomeric urea derivatives formed were separated by normal-phase high-performance liquid chromatography. Quantitation was performed by on-line ultraviolet detection at 275 nm and off-line radiometry.

Multiple inverse isotope dilution assay for oxprenolol and nine metabolites in biological fluids.

An isotope dilution assay for the specific determination of 14C-labelled oxprenolol and nine of its metabolites in the same biological sample is described. After addition of unlabelled carriers to the sample, oxprenolol and the metabolites were isolated by base- and acid-specific extraction and separated by normal-phase high-performance liquid chromatography using two different mobile phases. Quantitation of the various peaks was performed by on-line ultraviolet detection at 275 nm and off-line radiometry by liquid scintillation counting.

Multiple inverse isotope dilution assay for the stereospecific quantitative determination of R(-) and S(+)-oxaprotiline in biological fluids.

An isotope dilution assay for the determination of both oxaprotiline enantiomers in biological samples after administration of the racemic mixture has been developed. The enantiomers were reacted with synthetically prepared, optically pure N-trifluoroacetyl-S(-)-prolyl chloride, followed by high-performance liquid chromatographic separation of the diastereoisomers formed. Quantitation was performed by on-line UV detection at 260 nm and off-line radiometry by liquid scintillation counting.

Species differences in the disposition and metabolism of sulfinpyrazone.

1. The disposition and metabolism of sulfinpyrazone have been studied in rats, guinea-pigs, rabbits, dogs, rhesus monkeys and miniature swine after intravenous administration of 100 mg/kg of 14C-labelled drug. 2.

New metabolites of sulfinpyrazone in man.

The disposition and metabolism of sulfinpyrazone have been studied after oral administration of 100 mg 14C-labelled drug to two male volunteers. The results confirmed earlier observations on the kinetics and biotransformation of the drug in man. Additionally, four new metabolites were identified and quantified, i.