G. E. von Unruh

Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D,L-verapamil using stable isotope-labelled verapamil

SummaryFollowing i. v. administration, the plasma concentration-time curve of verapamil could best be described by either a mono- or biexponential equation. Total plasma clearance (1.26 l/min) approached liver blood flow (1.5 l/min), so it can be concluded that its clearance is liver blood flow-dependent. Although absorption was almost complete after oral administration, absolute bioavailability (20%) was low, due to extensive hepatic first-pass metabolism. The approach using stable isotope-labelled and unlabelled drug permits simultaneous administration by the intravascular and extravascular routes, thus allowing determination of absolute bioavailability in a single experiment.

Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy

The kinetics of carbamazepine using 15N‐carbamazepine were investigated in epileptic patients during combined anticonvulsant therapy. The 15N‐carbamazepine plasma half‐lives ranged from 5.0 to 13.6 hr with a mean of 8.2 hr. These half‐lives are appreciably shorter than reported during chronic carbamazepine monotherapy. Predicted steady‐state plasma levels and observed plasma levels of carbamazepine were in excellent agreement. Between 32% and 61% of the dose administered is excreted in the urine as carbamazepine‐trans‐diol, 5.2% to 8.8% as 9‐hydroxymethyl‐10‐carbamoyl acridane, 1% to 1.4% as 10,‐11‐carbamazepine epoxide, and 0.5% as carbamazepine. The data indicate that it is the epoxide‐diol pathway which is induced during long‐term treatment. Concomitant therapy with primidone, phenytoin, phénobarbital, ethosuximide, or methsuximide further induces carbamazepine metabolism.

Pharmacokinetics of oxcarbazepine and 10-hydroxy-carbazepine in the newborn child of an oxcarbazepine-treated mother

SummaryGaschromatography — mass spectrometry (GC/MS) was used to determine plasma levels of oxcarbazepine (OCB) and its main metabolite in a newborn girl and her OCB-treated mother during the first five post partum days.At delivery the maternal and neonatal plasma concentrations were in the same range, indicating considerable placental transfer of both substances. In spite of ingestion of both substances via breast milk, there was no accumulation in the baby. On the fifth post partum day OCB and 10-hydroxy-carbazepine (10-OH-CB) levels in plasma in the newborn were only 12 and 7%, respectively, of the values found on the first day after delivery.

Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination

SummaryAlthough the absorption of verapamil is almost complete after oral administration, its bioavailability is low due to extensive hepatic first-pass metabolism. Besides large interindividual differences in first-pass metabolism, pronounced day-to-day intraindividual variations in first-pass metabolism are observed, leading to erroneous results in relative bioavailability studies. Stable isotope techniques, which permit simultaneous administration of a solution and a tablet, can successfully be used to overcome these difficulties. The method has the advantage that two experiments can be carried out in a single test. Furthermore, the number of subjects required in bioavailability studies can be greatly reduced. Using this technique the bioavailability of verapamil tablets (Isoptin® 80) relative to a stable labelled solution of verapamil was found to be 108.1%, with a 95% confidence interval between 89.1 and 127.1%.

Use of stable labelled carbamazepine to study its kinetics during chronic carbamazepine treatment

SummaryThe kinetics of carbamazepine using stable labelled 15N-carbamazepine was studied in 4 epileptic patients who had been treated with it for at least 6 months. There was a decrease in half-life (12.3±0.8 h) and an increase in total plasma clearance (58.0±6.5 ml/min) as compared to single dose studies, which provide further evidence that carbamazepine induces its own metabolism during long-term treatment. Analysis of the urinary metabolites indicated induction of the epoxide-trans-diol pathway. Predicted and observed steady-state plasma levels were in good agreement, thus demonstrating that the use of stable labelled drugs is a useful technique to elucidate changes in kinetics and metabolism which may occur in patients during long-term treatment.

Valproic acid disposition in epileptic patients during combined antiepileptic maintenance therapy.

SummaryA previously developed mass spectrometric method was used to measure, in the presence of the unlabeled drug, the fate of pulse dose of tetradeuterated valproic acid given to epileptic patients. By this means the disposition of valproic acid (VPA) was studied in several epileptic patients on maintenance therapy with VPA and at least one other antiepileptic drug. For 6 patients with 6 different antiepileptic drug combinations, the mean VPA half-life was only 6.2 h, as compared to about 15 h after a single dose. The mean plasma clearance in those patients was 16.4 ml/min. The volume of distribution was 0.14 l/kg, which did not differ from values found in single dose studies. The clinical relevance of these findings is pointed out.

Experience with the [13C2]Oxalate Absorption Test

Abstract Hyperoxaluria is the most important risk factor for a formation of calcium oxalate-urinary stones. Usually, the bulk of oxalate will be formed in the human body, but in many patients the oxalate from food plays the decisive role. Conventionally, in urine the endogenous oxalate can not be distinguished from food derived oxalate. We have developed a standardized oxalate-absorption test, applying a physiological dose (50 mg disodium salt of [13C2]oxalic acid) of labelled oxalate. The assay has been published. Now we report on the first extensive applications of this test in 86 volunteers and 135 patients from different groups with calcium oxalate stones or an increased risk of the formation of such stones. In one-third of the patients with calcium oxalate-urinary stones an oxalate hyperabsorption was diagnosed. For these patients, a dietetic stone prophylaxis and/or therapy is indicated.

Isotope Effects during Metabolism of (+)- and (−)- Trans Tramadol Isotopomers by Human Liver Microsomes

Abstract As for the unlabelled (±)-1(e)-(m-methoxyphenyl)-2(e)-(dimethylaminomethyl)cyclohexane 1(a)-ol, tramadol, (T), pronounced stereochemical effects were observed for the isotopomers with regard to the extent of formation of O- and N-demethylated metabolites. The pharmacological active O-demethylated metabolite M1 was formed from the unlabelled as well as from the labelled (+)-tramadols about 6 times less than from the corresponding (−)-T. In contrast, the N-demethylated metabolite M2 was formed from the (+)-tramadols about 1.5 times more than from the corresponding (−)-T. These steric effects were modulated by the smaller apparent isotope effects for the isotopomers. Isotope effects were expressed as kH/kD (calculated from concentrations) and as DV, DV/K and HKm/DKm (from Eadie-Hofstee plots).

Isotope Effects During Metabolism of (±)-Tramadol Isotopomers by Human Liver Microsomes

Abstract Tramadol (T), racemic 1(e)-(m-methoxyphenyl)-2(e)-(dimethylaminomethyl)-cyclohexane-1(a)-ol is an effective analgesic drug. Metabolites were formed by O- and N-demethylation. Six deuterated tramadol isotopomers have been synthesized; their kinetic isotope effects in oxidative demethylation reactions were investigated in vitro using human liver microsomes. In comparison to unlabelled (±)-tramadol, (±)-T-OCD3 and (±)-T-D9 displayed an unequivocal (< 3), (±)-T-ND6 and (±)-T-ND3 a noticeable, and (±)-T-cyclohexyl-D3 as well as (±)-T-15ND2 no measurable isotope effect. Metabolic switching (favoring the N-demethylation) was observed only after incubation of a tramadol with a trideuterated methoxy group. Additional N-CD3-groups prevented this metabolic switching. Metabolic switching favoring the O-demethylation was not observed. The isoenzyme responsible for the O-demethylation was always saturated under the experimental conditions required to detect the metabolites. The two tramadol isotopomers contain...

Labelling Studies for Structure Elucidation of a New Hydroxymetabolite of Tramadol

Abstract Tramadol, racemic 1-(3-methoxyphenyl)-2-(dimethylaminomethyl)cyclohexane-1-ol, is an effective analgesic drug. Metabolites of tramadol described so far originate from O- and N-demethylation and are excreted in urine directly or after conjugation. A further metabolite was found in human liver microsome incubations and in the urine of volunteers after ingestion of tramadol. To elucidate the structure of the new metabolite, seven deuterated isotopomers of tramadol have been synthesized and ingested by volunteers. The mass spectra of the metabolites derived showed (i) that it was a hydroxy metabolite, (ii) that the hydroxy group was not located on the aromatic ring, the side chain, or the positions 2 and 6 of the cyclohexane ring, (iii) that the hydroxy-group was introduced to one of the the positions 3, 4 or 5 of the cyclohexane ring. The hydroxy metabolite was formed preferentially from the (-)-enantiomer, (1S,2S)-tramadol.