Literature Values of Terminal Half-Lives of Clozapine are Dependent on the Time of the Last Data Point

The pharmacokinetics of clozapine is a subject of intensive research because of its narrow therapeutic window and susceptibility to drug-drug interactions. A systematic literature search was conducted in PubMed and Google Scholar for half-life values of clozapine in humans. Twenty-one publications were found to contain terminal half-life information of clozapine in humans along with the time of the last plasma sample. Average values of the terminal half-lives of clozapine were calculated to be 10.2, 13.2, 14.2, 18.3 and 29.2 hours with a last data point at 12, 24, 48, 72 and 120 hours, respectively. This confirms the notion that one would arrive at longer terminal half-lives when longer blood sampling times are used in pharmacokinetic studies on clozapine. “Terminal half-lives” of therapeutic agent are routinely computed and reported in literature. For drugs with a third deep compartment such as clozapine, one should remember to consider the time of the last data point when comparing the “terminal” half-life.

Postdialytic Rebound of Serum Phosphorus: Pathogenetic and Clinical Insights

ABSTRACT. To gain insights into postdialytic rebound of serum phosphate (PDR-P), serum phosphate (P), calcium (Ca), and parathyroid hormone (PTH), levels were compared from the end of treatment (T0) to the subsequent 30 to 120 min and up to 68 hr in uremic patients who underwent with crossover modality a single session of two dialytic treatments characterized by different convective removal: standard hemodialysis (HD) and hemodiafiltration (HDF). In HDF,versusHD, P removal was greater (1171 ± 90versus814 ± 79 mg;P< 0.05) in the presence of similar predialytic P levels (6.0 ± 0.2 and 5.9 ± 0.4 mg/dl) and Kt/V (1.35 ± 0.06 and 1.34 ± 0.05); however, the serum P values at T0 did not differ (3.0 ± 0.2versus3.3 ± 0.2 mg/dl). In HDF, PDR-P was more rapid (30 minversus90 min) and of a greater extent (at T120: +69 ± 6%versus+31 ± 4%;P< 0.0001). The higher P levels were maintained throughout the interdialytic period. Ca × P and PTH changed in parallel. Thereafter, patients were randomized to receive either HD or HDF for 3 mo. During this period, in the presence of similar Kt/V, protein intake, and dose of phospate binder, predialytic serum P levels diminished in HDF (from 5.8 ± 0.2 to 4.4 ± 0.3 mg/dl;P< 0.05), but they remained unchanged in HD. A similar pattern of changes was detected in Ca × P. Therefore, PDR-P is likely dependent on the mobilization of phosphate from a deep compartment induced by the intradialytic removal of this solute. Enhancement of convective removal acutely amplifies the entity of the phenomenon but allows a better control of Ca-P homeostasis in the medium term.

The Long Saphenous Vein Compartment

Objective: To define the relationship between the long saphenous vein and the connective framework of the subcutaneous tissue (hypodermis) of the lower limb. Methods: The connective skeleton of the hypodermis was studied by anatomical dissection, stereomicroscopy of cross-sectioned specimens and ultrasound imaging in 88 lower extremities. Results: The long saphenous vein runs for most of its length in a narrow compartment delineated deeply by the muscular fascia and superficially by a connective tissue lamina descending from the inguinal ligament in the anteromedial part of the thigh and medial aspect of the calf. These two fascia fuse at the boundaries of the compartment. The long saphenous vein adventitia is anchored to both fasciase by thick connective tissue strands. Conclusion: The anatomical relationship between the long saphenous vein and the connective framework of the hypodermis suggests that: (1) only the vein running within the deep compartment of the hypodermis should be considered as the ‘true’ long saphenous vein; (2) the other subcutaneous veins running outside the compartment should be considered as collaterals of the long saphenous vein; (3) the connective sheath surrounding the long saphenous vein could oppose dilatation of this vessel should valvular incompetence develop; and (4) thigh muscle contraction could modify the calibre of the long saphenous vein as happens in the deep veins. Finally, the authors propose to term the deep compartment of the medial thigh and the leg hypodermis the ‘long saphenous vein compartment’ and consequently the hypodermic connective lamina, by which it is superficially delimited, as the ‘long saphenous vein fascia’.

Placental Transfer of Theophylline: Two Case Reports

The placental transfer of xanthine compounds such as caffeine and theophylline has only recently been recognized. By measuring serum theophylline concentrations in two mothers and their neonates at delivery, we have attempted to determine the extent and significance of placental theophylline transfer to the fetus. At delivery, the two maternal serum theophylline concentrations were 13 µg/ml and 11 µg/ml, and cord serum contained 12 µg/ ml and 11 µg/ml of theophylline, respectively. In our first case, the neonatal theophylline concentration at delivery was not reported, but a concentration of 13 µg/ml was obtained six hours after delivery. In the second case, the neonatal serum contained 14 µg/ml of theophylline at delivery, 3 µg/ml higher than the cord or maternal serum concentration. It is possible that the fetus behaves as a pharmacokinetically "deep" compartment with slower drug elimination relative to maternal excretion. Serial serum theophylline concentrations in the neonates were determined at 6, 18, 30, and 40 hours after delivery. For the first 18 hours of life, both neonates' serum contained theophylline within or very close to the therapeutic range (10 to 20 µg/ml) in adults and children. Both neonates reported on in this article had minor clinical symptoms that may have been related to the theophylline present in their serum. Neonates of mothers receiving theophylline products should be monitored for the pharmacologic actions of theophylline.

BIODYNAMICS OF 1.2α-METHYLENE-6-CHLORO-PREGNA-4,6-DIEN-17α-OL-3,20-DIONE (CYPROTERONE) IN MAN FOLLOWING ORAL AND INTRAVENOUS ADMINISTRATION

ABSTRACT The metabolism and pharmacokinetics (biodynamics) of 1,2α-methylene-[14C]-6-chloro-pregna-4,6-dien-17α-ol-3,20-dione (Cyproterone; Cy) have been investigated in man following intravenous and oral administration. The principal metabolite in the plasma following the intravenous and oral administration is 1,2α-methylene-6-chloro-pregna-4,6-diene-17α,20α-diol-3-one (20α-OH-Cy). After a single oral dose of 100 mg Cy, the concentration of unchanged free Cy during the first 24 hours is about 1 μg/100 ml plasma. Of 100 mg Cy administered p. o., only about 40% was absorbed, 60% being eliminated in the faeces. In the urine, 20α-OH-Cy and 1,2α-methylene-6-chloro-androst-4,6-diene-3,17-dione(17-keto-Cy) were isolated and identified as the principal metabolites. About 60% of the radioactivity in the urine, following oral and intravenous administration of [14C]-Cy, is present in the form of watersoluble compounds (conjugates) which cannot be decomposed either with enzymes (β-glucuronidase, sulphatase) or by means of cold or hot acid hydrolysis. Decomposition by solvolysis with perchloric acid in ethyl acetate, however, is quantitative. On the basis of simulation performed with an analogue computer, the elimination half-life of the deep compartments following intravenous or oral administration of Cy would be between 3 and 5 days, on the basis of 14C-activity. 'Oral administration' of 100 mg Cy daily, as simulated on the analogue computer, is cumulative; an equilibrium in the deep compartment being reached only after about 28 days and that in the blood after about 14 days.