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Mehrere Studien wiesen eine Beteiligung der Enzyme CYP2D6, CYP2C19 und CYP2C9 am Metabolismus von trizyklischen Antidepressiva nach. Wir untersuchten die Auswirkungen genetischer Polymorphismen dieser Enzyme auf die Pharmakokinetik von E-, Z-Doxepin und Trimipramin beim Menschen. Eine einzelne orale Dosis von jeweils 75 mg Trimipramin und Doxepin wurde 42 gesunden Probanden verabreicht, die als Schnell- (EM), Intermediär- (IM) und Langsammetabolisierer (PM) von CYP2D6- und CYP2C19-Substraten und als Langsammetabolisierer mit dem CYP2C9-Genotyp *3/*3 genotypisiert worden waren. Die Substrate sowie ihre aktiven Metaboliten wurden mittels HPLC im Plasma gemessen, Daten wurden mit nonparametrischen pharmakokinetischen Methoden analysiert und statistisch ausgewertet. Die mittlere E-Doxepin-Clearance (95%-KI) betrug 406 (390-445), 247 (241-271) and 127 (124-139) l/h bei CYP2D6-EMs, -IMs und –PMs und war auch bei Trägern des CYP2C9*3/*3-Genotyps signifikant niedriger (238 l/h). CYP2C19 beeinflusste die orale Clearance von Z-Doxepin um das 2,5-fache (73 l/h in CYP2C19-PMs verglichen mit 191 l/h bei EMs). Die AUC (0-48h) des aktiven Metaboliten Desmethyldoxepin war vom CYP2D6-Genotyp abhängig mit einem Median von 5,28, 1,35 und 1,28 nmol/l*h bei CYP2D6-PMs, -IMs und –EMs. Die mittlere orale Trimipramin-Clearance betrug 276 l/h (180-444) in der Referenzgruppe aber nur 36 l/h (24-48) bei CYP2D6-PMs. Die AUC von Desmethyltrimipramin war 40-fach höher bei CYP2D6-PMs als bei EMs (1,7 verglichen mit 0,04 mg/l*h bei EMs), aber unter der Nachweisgrenze bei den meisten Probanden mit CYP2C19- oder CYP2C9-Defizienz. Der CYP2D6-Polymorphismus wies eine starke Auswirkung auf die Pharmakokinetik von E-Doxepin und Trimipramin sowie eine ausgeprägte Stereoselektivität bei der Biotransformation von Doxepin auf. CYP2D6-PMs sind möglicherweise einem erhöhten Risiko für unerwünschte Nebenwirkungen ausgesetzt bei der Behandlung mit den EMpfohlenen Dosen dieser Antidepressiva., Several studies have demonstrated involvement of the enzymes CYP2D6, CYP2C19 and CYP2C9 in the metabolism of tricyclic antidepressants. We studied the effects of genetic polymorphisms in these enzymes on E-,Z-doxepin and trimipramine pharmacokinetics in humans. A single orale dose of each 75 mg timipramine and doxepin was given to 42 healthy volunteers genotyped as extensive (EM), intermediate (IM) and poor (PM) metabolizers of substrates of CYP2D6 and of CYP2C19 and as slow metabolizers with the CYP2C9 genotype *3/*3. E-,Z-doxepin and -desmethyldoxepin as well as trimipramine and desmethyltrimipramine were quantified in plasma by HPLC. Data were analyzed by non-parametric pharmacokinetics and statistics. Mean E-doxepin clearance (95% confidence interval) was 406 (390-445), 247 (241-271) and 127 (124-139) l/h in EMs, IMs and PMs of CYP2D6 and was also significantly lower in carriers of CYP2C9*3/*3 (238 l/h). CYP2C19 was involved in Z-doxepin metabolism with 2.5-fold differences in oral clearances (73 l/h in CYP2C19 PMs compared with 191 l/h in EMs). The AUC (0-48 h) of the active metabolite desmethyldoxepin was dependent on CYP2D6 genotype with a median of 5.28, 1.35 and 1.28 nmol/l*h in PMs, IMs and EMs of CYP2D6. The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans. The median oral clearance of trimipramine was 276 l/h (180-444) in the reference group but only 36 l/h (24-48) in CYP2D6-PMs. The AUC of desmethyltrimipramine was 40-fold greater in CYP2D6 PMs than in the reference group (1.7 vs. 0.04 mg/l*h in EMs), but below the quantification limit in most carriers of deficiencies of CYP2C19 or CYP2C9. The CYP2D6 polymorphism had a strong impact on E-doxepin and trimipramine pharmacokinetics and CYP2D6-PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses of these antidepressants.

The goal of this paper is to expand the knowledge about the functional anatomy of the male genital system of actinotrichid mites and to contribute to phylogenetic questions. Histological studies were carried out on three taxa: Ameronothrus lineatus (Oribatida, Brachypylina), Linopodes spec. (Prostigmata, Eupodoidea) and Tydeus californicus (Prostigmata, Tydeoidea).The proximal genital system of the taxa shows a rather consistent arrangement, which is in agreement to those of other Actinotrichida. It consists of a testis, which is divided into a germinal and a glandular part, and paired vasa deferentia which fuse before leading into the ductus ejaculatorius.The distal genital system of the three taxa consists of a ductus ejaculatorius and a genital chamber, with some profound differences in the specific arrangements of Oribatida and Prostigmata. There is no evidence for homology of the particular structures in both taxa. The ductus ejaculatorius of Linopodes spec. is divided into three chambers, an arrangement which is known from other Prostigmata as well as from Endeostigmata. Furthermore, an unpaired anterior accessory gland can be found in Linopodes spec. and Tydeus californicus, which is also known from other prostigmatid and endeostigmatid mites. Thus, the formation of spermatophores of Linopodes spec. is probably homologous to that described from other Prostigmata.Ultrastructural results of the accessory organ of Ameronothrus lineatus do not give any evidence for a glandular function of this organ, as hypothesized in previous studies.The spermatozoa of Ameronothrus lineatus exhibit structures typical for higher oribatida, i.e., loss of an acrosome complex, modification of mitochondria and possession of electron dense bodies. In the spermatogenesis of Linopodes spec. and Tydeus californicus, some characteristics can be found, which support a close relationship of Eupodoidea and Tydeoidea.

The goal of this paper is to expand the knowledge about the functional anatomy of the male genital system of actinotrichid mites and to contribute to phylogenetic questions. Histological studies were carried out on three taxa: Ameronothrus lineatus (Oribatida, Brachypylina), Linopodes spec. (Prostigmata, Eupodoidea) and Tydeus californicus (Prostigmata, Tydeoidea).The proximal genital system of the taxa shows a rather consistent arrangement, which is in agreement to those of other Actinotrichida. It consists of a testis, which is divided into a germinal and a glandular part, and paired vasa deferentia which fuse before leading into the ductus ejaculatorius.The distal genital system of the three taxa consists of a ductus ejaculatorius and a genital chamber, with some profound differences in the specific arrangements of Oribatida and Prostigmata. There is no evidence for homology of the particular structures in both taxa. The ductus ejaculatorius of Linopodes spec. is divided into three chambers, an arrangement which is known from other Prostigmata as well as from Endeostigmata. Furthermore, an unpaired anterior accessory gland can be found in Linopodes spec. and Tydeus californicus, which is also known from other prostigmatid and endeostigmatid mites. Thus, the formation of spermatophores of Linopodes spec. is probably homologous to that described from other Prostigmata.Ultrastructural results of the accessory organ of Ameronothrus lineatus do not give any evidence for a glandular function of this organ, as hypothesized in previous studies.The spermatozoa of Ameronothrus lineatus exhibit structures typical for higher oribatida, i.e., loss of an acrosome complex, modification of mitochondria and possession of electron dense bodies. In the spermatogenesis of Linopodes spec. and Tydeus californicus, some characteristics can be found, which support a close relationship of Eupodoidea and Tydeoidea.

The goal of this paper is to expand the knowledge about the functional anatomy of the male genital system of actinotrichid mites and to contribute to phylogenetic questions. Histological studies were carried out on three taxa: Ameronothrus lineatus (Oribatida, Brachypylina), Linopodes spec. (Prostigmata, Eupodoidea) and Tydeus californicus (Prostigmata, Tydeoidea).The proximal genital system of the taxa shows a rather consistent arrangement, which is in agreement to those of other Actinotrichida. It consists of a testis, which is divided into a germinal and a glandular part, and paired vasa deferentia which fuse before leading into the ductus ejaculatorius.The distal genital system of the three taxa consists of a ductus ejaculatorius and a genital chamber, with some profound differences in the specific arrangements of Oribatida and Prostigmata. There is no evidence for homology of the particular structures in both taxa. The ductus ejaculatorius of Linopodes spec. is divided into three chambers, an arrangement which is known from other Prostigmata as well as from Endeostigmata. Furthermore, an unpaired anterior accessory gland can be found in Linopodes spec. and Tydeus californicus, which is also known from other prostigmatid and endeostigmatid mites. Thus, the formation of spermatophores of Linopodes spec. is probably homologous to that described from other Prostigmata.Ultrastructural results of the accessory organ of Ameronothrus lineatus do not give any evidence for a glandular function of this organ, as hypothesized in previous studies.The spermatozoa of Ameronothrus lineatus exhibit structures typical for higher oribatida, i.e., loss of an acrosome complex, modification of mitochondria and possession of electron dense bodies. In the spermatogenesis of Linopodes spec. and Tydeus californicus, some characteristics can be found, which support a close relationship of Eupodoidea and Tydeoidea.