Achim Schmoldt

The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment

SummaryFlutamide is a nonsteroidal antiandrogen used in the treatment of prostatic carcinoma. We have investigated the disposition of flutamide and its two major metabolites in ten urological in-patients without significant liver or renal disease.After oral administration flutamide is absorbed from the gastrointestinal tract with a tmax of about 2 h.Flutamide undergoes extensive first-pass metabolism, and its major metabolites are 2-hydroxyflutamide and the hydrolysis product 3-trifluoromethyl-4-nitroaniline.After the oral administration of a single dose of 250 mg or 500 mg maximum flutamide plasma concentrations of 0.02 and 0.1 µg·ml−1 respectively were observed. Maximum plasma concentrations of 2-hydroxylfutamide for the same flutamide doses were 1.3 and 2.4 µg·ml−1 (mean ofn=2 orn=3).Steady-state concentrations of the biologically active metabolite 2-hydroxyflutamide (0.94±0.23 µg·ml−1, mean±SD,n=5) were found at 2–4 days after the administration of 250 mg every 8 h.The area under the plasma concentration time curve for 2-hydroxyflutamide averaged 11.4 (10.6 and 12.1) and 24.3 (21.5–29.4,n=3) µg·ml−1·h for 250 mg and 500 mg flutamide orally.2-Hydroxyflutamide and 3-trifluoromethyl-4-nitroaniline were eliminated monoexponentially with half-times of 4.3–21.9 and 4.3–17.2 h (n=5) respectively.

The metabolism of pyrene by rat liver microsomes and the influence of various mono-oxygenase inducers

1. Pyrene metabolite g.l.c. profiles were recorded and metabolites identified by mass spectrometry. 2. Pyrene is metabolized by liver microsomes of untreated rats to 1-hydroxypyrene, 4,5-dihydroxy-4,5-dihydropyrene, two different diphenols and a triol, tentatively identified as 1,4,5-trihydroxy-4,5-dihydropyrene. 3. Pretreatment with phenobarbital or polychlorinated biphenyls favours oxidation at the K-region, whereas cytochrome P-448 inducers stimulate oxidation at the non-K-region of pyrene. 4. 1-Hydroxypyrene does not inhibit pyrene oxidation. 5. Pyrene diphenols are formed by secondary oxidation of 1-hydroxypyrene. 6. Triols are formed from dihydrodiols by secondary oxidation.

Gamma-Hydroxybutyrate in Urine and Serum: Additional Data Supporting Current Cut-Off Recommendations

Besides the use of Gamma-Hydroxybutyrate (GHB) as a recreational drug, use of GHB as an agent in drug-facilitated crime should also be considered. In these cases, there is often a delay of several hours from the incident to collection of the samples. As GHB has a very short plasma half-life, the window of detection is small and in the majority of these specimens, levels of GHB are low. Because GHB is naturally occurring in humans, discrimination between endogenous and exogenous GHB is complicated, particularly in those samples with low concentrations. In this study, endogenous GHB levels of 50 serum and 50 urine samples were determined by GC-MS after conversion to trimethyl-silyl-derivatives. Concentrations in serum ranged from 0.62 to 3.24 mg/L (mean=1.14 mg/L; median=0.97 mg/L) and from 0.64 to 4.20mg/L (mean=1.21 mg/L; median=0.96 mg/L) in urine. Based on this substantial data, the current suggested lower cut-off of 4 mg/L in ante mortem serum samples could be confirmed. For urine, we propose the lower cut-off of 6 mg/L instead of 10mg/L to avoid false negative interpretation.

Influence of monooxygenase inducers on the metabolic profile of phenanthrene in rat liver microsomes

The oxidation of phenanthrene by rat liver microsomes significantly depends on the pretreatment of the animals as shown by means of gas chromatography/mass spectrometry. Whereas untreated animals convert phenanthrene exclusively into the 9,10-dihydrodiol (K-region), pretreatment with various polycyclic aromatic hydrocarbons and related compounds resulted in different rates of additional oxidation at the 1,2- and 3,4-position. Moreover, secondary metabolism to dihydrodiol epoxides, detected as triols, was observed. Despite considerable concentration of the proximate carcinogen of phenanthrene (1,2-dihydrodiol) only low concentrations of the ultimate carcinogen were detected which may explain the carcinogenic inefficiency of this hydrocarbon.

Induction of rat liver enzymes by polychlorinated biphenyls (PCBs) in dependence on the dose and chlorine content

In order to study the influence of the chlorine content of polychlorinated biphenyls (PCBs) on the induction of microsomal mixed-function oxidases, dose-response curves for di-, tetra- and hexachlorobiphenyl mixtures were plotted. For this purpose, the activity of enzymes was measured after a single administration of each dose at the time of maximum induction (2 to 4 days, depending on the dose and the chlorine contents). After treatment with di-, tetra- and hexachlorobiphenyl, respectively, the following effects were measured (controls = 100%): 260%, 320%, 300% for cyt. P450; 185%, 205%, 200% for NADPH-dependent cyt.c.reductase; 645%, 620%, 640% for oxidative demethylation of p-nitroanisole; 400%, 480%, 440% for aniline hydroxylase. The dose-response curves for the compounds are parallel, and hexachlorobiphenyls proved to be most potent. At half the maximal levels the ratio of di- : tetra- : hexachlorobiphenyl in terms of reciprocal doses was found to be 1∶2.2∶22 for Cyt. P450, 1∶3.5∶9 for demethylation rate of p-nitroanisole, and 1∶1.2∶5 for aniline hydroxylase.Gaschromatographic analyses of PCB residues of the livers revealed a considerably lower excretion rate for the higher chlorinated compounds. Thus, apart from their specific inducing activity, the prolonged exposure to these compounds may explain the inducing capacity. After almost all doses of each PCB, liver concentrations exceed the in-vitro concentration necessary for 50% competitive inhibition of the p-nitroanisole (0.1 mM) demethylation rate.ZusammenfassungUm den Einfluß des Chlorgehaltes polychlorierter Biphenyle (PCB) auf die Induktion mikrosomaler mischfunktioneller Oxidasen zu untersuchen, sollten Dosis-Wirkungsbeziehungen für Di-, Tetra- und Hexachlorbiphenylgemische gemessen werden. Dazu wurde nach einmaliger i.p. Applikation der PCB-Dosis die Aktivität der Enzyme jeweils zum Zeitpunkt der maximalen Induktionseflekte (abhängig vom Chlorierungsgrad und der Dosis 2 bis 4 Tage nach der Applikation) bestimmt. Die maximal erreichten Werte betrugen (Kontrollen = 100 %) nach Gabe von Di-, Tetra- bzw. Hexachlorbiphenyl für Cytochrom P450: 260%, 320%, 360%; für die NADPH-abhängige Cytochrom-c-Reduktase: 185%, 205%, 200%; für die oxydative Demethylierung von p-Nitroanisol: 645%, 620%, 640%; für die Anilinhydroxylase: 400%, 480%, 440%. Die Dosis-Wirkungskurven sind zueinander parallel verschoben und erweisen das Hexachlorbiphenyl als bei weitem am wirksamsten. Zur Erzielung halbmaximaler Effekte verhalten sich die reziproken Dosen von Di-: Tetra-: Hexachlorbiphenyl wie 1∶2.2∶22 für Cyt. P450; 1∶3.5∶9 für die p-Nitroanisoldemethylierung und 1∶1.2∶5 für die Anilinhydroxylase.Gaschromatographische Analysen der PCB-Rückstände in der Leber zeigen eine erheblich langsamere Elimination der hochchlorierten Komponenten, so daß diese neben ihrer spezifischen Wirkungsstärke den Induktionsmechanismus wesentlich länger unterhalten können. Die Konzentrationen überschreiten nach den meisten Dosierungen aller drei PCBs die in vitro erforderliche Konzentration von 50 μM zur kompetitiven 50%igen Hemmung der p-Nitroanisol-Demethylierung (0,1 mM).

Digitoxin metabolism by rat liver microsomes

Background: Malnutrition among hospitalized patients increases length of stay (LOS) and carries extra hospitalization costs. Objective: To review the impact of malnutrition on hospital LOS and costs in Europe. Methods: PubMed and Google Scholar search. All articles from January 2004 until November 2014 were identified. Reference lists of relevant articles were also manually searched. Results: Ten studies on LOS and nine studies on costs were reviewed. The methods used to assess malnutrition and to calculate costs differed considerably between studies. Malnutrition led to an increased LOS ranging from 2.4 to 7.2 days. Among hospitalized patients, malnutrition led to an additional individual cost ranging between 1640 V and 5829 V. At the national level, the costs of malnutrition ranged between 32.8 million V and 1.2 billion V. Expressed as percentage of national health expenditures, the values ranged between 2.1% and 10%. Conclusions: In Europe, malnutrition leads to an increase in LOS and in hospital costs, both at the individual and the national level. Standardization of methods and results reported is needed to adequately compare results between countries. © 2015 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

Fentanyl: Toxic or Therapeutic? Postmortem and Antemortem Blood Concentrations After Transdermal Fentanyl Application

In forensic toxicology, several fatal intoxications with fentanyl have occurred in the recent past, but there are rare discussions in the literature of postmortem fentanyl blood concentrations subsequent to lethal and non lethal applications. To study this problem, we analyzed postmortem blood concentrations (vena femoralis) of 118 cases with therapeutic use of fentanyl and compared them with serum levels of 27 living persons after therapeutic administration of fentanyl patches (Durogesic). Basically, blood concentrations in postmortem specimens cannot be directly compared with in vivo serum levels: in our study, we observed that postmortem fentanyl blood concentrations were on average up to nine times higher than in vivo serum levels at the same dose. These differences could be explained by postmortem redistribution, but they were higher than expected on the basis of the physical and chemical properties of fentanyl alone. The special pharmacokinetics of the drug after long term transdermal application seem to play an important role in this phenomenon. In addition, there was no clear correlation between transdermal fentanyl dose and blood or serum concentrations, either antemortem or postmortem. Our study provides extensive data for postmortem peripheral blood concentrations after therapeutic non-fatal fentanyl patch application and demonstrates once more that in forensic toxicology, blood concentrations must be holistically interpreted with respect to all aspects of a case.

The metabolism of foreign compounds in rats after treatment with polychlorinated biphenyls (PCBs).

Abstract Pretreatment of rats with a single dose of polychlorinated biphenyls caused an increase in the activity of UDP glucuronyltransferase (EC 2.4.1.17; acceptor unspecific) in liver microsomes towards the substrates p-nitrophenol and 4-methylumbelliferone. The results of kinetic experiments suggest enhanced enzyme activity is caused by enzyme induction. The effect was dependent on dose and chlorine content of the polychlorinated biphenyls administrated. The time course of UDP glucuronyltransferase activity after a single dose of polychlorinated biphenyls demonstrated a long lasting effect. Elevated biliary excretion of sulfobromophthalein conjugates after pretreatment with polychlorinated biphenyls was also demonstrated. In addition bile flow per g liver was increased and sulfobromophthalein concentration in serum and liver was reduced. Maximum effects were observed three days after treatment; thereafter these parameters slowly returned to normal levels.

On the metabolic activation of benz[a]acridine and benz[c]acridine by rat liver and lung microsomes

The metabolism of benz[a]- and benz[c]acridine by liver and lung microsomes from untreated, phenobarbital (PB)-treated and benzo[k]fluoranthene (BkF)-treated rats has been studied by gas chromatography/mass spectrometry (GC/MS). Epoxidation and hydrolysis of the epoxides to dihydrodiols were found to be the predominant pathways for all substrates. N-Oxidation is likely to occur in the case of benz[c]acridine. However, no unequivocal evidence could be obtained for the formation of the ultimate carcinogens--the t-3,4-dihydrodiol-1,2-epoxides--in case of both benz[a]- and benz[c]acridine. K-Region oxidation was induced by phenobarbital, whereas the formation of non-K-region metabolites increased after BkF treatment in the case of benz[c]acridine.

Rauschgifttodesfälle mit Methadonbeteiligung (Hamburg 1990–1996)

Abstract The ca. 1000 drug-related fatalities that were examined in Hamburg from 1990–1996 by the Institute of Legal Medicine were analysed with respect to consumption of substitute drugs such as methadone. The incidence of methadone-related fatalities has increased in the last two years. The highest incidence was found in 1995 when methadone was detected in the blood of about 20% of all drug-related fatalities. Lethal monointoxications or combined intoxications with a dominant role of methadone were experienced rarely (about 1% of all drug-related fatalities). Of the persons who were enroled since 1990 in a methadone maintenance programme 2% have been registered as drug- related fatalities. The mortality of street addicts without comparable medical help was about 10% in the same period. There is further need for improved methods of registration, documentation and forensic/sociological analysis of all drug-related fatalities for reliable conclusions concerning mortality rates of drug users who are enroled in methadone maintenance programmes.Zusammenfassung Unter dem Aspekt des Konsums von Ersatzdrogen (insbesondere Methadon) wurden die ca. 1000 Hamburger Rauschgifttodesfälle im Zeitraum 1990– 1996 retrospektiv analysiert. Die Anzahl der Drogentodesfälle mit chemisch-toxikologischem Nachweis eines Methadon- (Begleit-) Konsums zeigt eine stark ansteigende Tendenz. Die bislang höchste Inzidenz des Methadonnachweises zeigte sich im Jahr 1995 mit ca. 20% aller Drogentoten. Tödliche Monointoxikationen bzw. Mischintoxikationen, bei denen Methadon relevant an der Gesamttoxizität der nachgewiesenen Drogen beteiligt war, wurden nur höchst vereinzelt beobachtet (bisher ca. 1% aller Drogentodesfälle). Von den bei der Hamburger Ärztekammer registrierten Methadon-Substituierten sind bisher ca. 2% verstorben; die Letalität der Drogenkonsumenten ohne Substitution sowie entsprechende institutionelle Anbindung und Hilfe liegt dagegen bei ca. 10% im Untersuchungszeitraum. Für weitergehende Schlußfolgerungen und Verallgemeinerungen zum Sterberisiko Methadonsubstituierter bedarf es einer exakten Erfassung, Dokumentation sowie einer rechtsmedizinischen und sozialwissenschaftlichen Analyse aller Drogentodesfälle bzw. gezielter Kohortenstudien.In Deutschland wird zunehmend über Rauschgifttodesfälle mit Methadonnachweis berichtet [12, 14]. Die Letalität ist ein vergleichsweise hartes Kriterium der Qualitätskontrolle, das auch mit geringerer Latenz Therapieeffekte sichtbar machen kann. Sie sagt zweifellos wenig über Lebensqualitätsaspekte aus, doch spiegelt sie den grundlegensten Anspruch der therapeutischen Seite wider: Zunächst das Überleben der Drogenabhängigen zu sichern, um darauf aufbauend eine langfristige psychosoziale Rehabilitation zu verwirklichen. Die Einschätzung der Letalität in einem unbehandelten Vergleichskollektiv ist jedoch nicht unproblematisch, wenn es – wie bei den i.v. Drogenabhängigen – nicht einmal einheitliche Schätzungen der Grundgesamtheit gibt. Hamburg hat eine seit Jahren anhaltend hohe Rauschgiftletalität zu verzeichnen, die in den Jahren bis 1992 stark anstieg, um sich dann auf erhöhtem Niveau zu stabilisieren (Abb. 1). Hier war seit 1990 eine vergleichsweise intensiv betriebene Ausweitung der Methadonsubstitution zu beobachten, bis die Kostenträger Anfang 1996 ihre weitere Unterstützung einschränkten. Da der Stadtstaat Hamburg räumlich und administrativ gut überschaubar ist, ist davon auszugehen, daß sich die Effekte dieses Therapieangebotes gut abbilden lassen und auch im Bereich der Letalität widerspiegeln lassen.