Isolation and identification of clozapine metabolites in patient urine.

Biotransformation products of the atypical neuroleptic clozapine were isolated from urine samples of three schizophrenic patients by solid-phase extraction, liquid-liquid extraction for the separation of unpolar and polar metabolites, and thin-layer chromatography followed by final purification by high-performance liquid chromatography. Their structures were elucidated by mass spectrometry and (1)H NMR spectroscopy and in some cases by enzymatic deconjugation. Besides the known metabolites desmethylclozapine, clozapine N-oxide, 8-deschloro-8-hydroxyclozapine, and 8-deschloro-8-hydroxydesmethylclozapine, the unpolar fraction contained 7-hydroxyclozapine and a compound in which the piperazine ring of clozapine was partially degraded to an ethylenediamine derivative. Novel metabolites identified in the polar fraction were the sulfate and glucuronide conjugates of 7-hydroxyclozapine N-oxide, 8-deschloro-8-hydroxyclozapine-O-glucuronide, and the O-glucuronide of N-hydroxydesmethylclozapine; further conjugates were tentatively identified as 9-hydroxydesmethylclozapine-O-sulfate and 6-hydroxyclozapine-O-sulfate. In addition, the previously described conjugates 7-hydroxydesmethylclozapine-O-sulfate, 7-hydroxyclozapine-O-glucuronide and -O-sulfate, 8-deschloro-8-hydroxydesmethylclozapine-O-glucuronide, and the quaternary ammonium glucuronide of clozapine were detected.

Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance.

AIMS: N-Desmethylclozapine and clozapine N-oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney. METHODS: From 15 psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2 h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis. RESULTS: The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N-desmethylclozapine 9.7%, and clozapine N-oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N-desmethylclozapine and clozapine N-oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N-desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose. CONCLUSIONS: Clozapine, N-desmethylclozapine and clozapine N-oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N-demethylation and N-oxidation must make major contributions to the total fate of clozapine in patients.

An overview of venus geology.

The Magellan spacecraft is producing comprehensive image and altimetry data for the planet Venus. Initial geologic mapping of the planet reveals a surface dominated by volcanic plains and characterized by extensive volcanism and tectonic deformation. Geologic and geomorphologic units include plains terrains, tectonic terrains, and surficial material units. Understanding the origin of these units and the relation between them is an ongoing task of the Magellan team.

Venus volcanism: initial analysis from magellan data.

Magellan images confirm that volcanism is widespread and has been fimdamentally important in the formation and evolution of the crust of Venus. High-resolution imaging data reveal evidence for intrusion (dike formation and cryptodomes) and extrusion (a wide range of lava flows). Also observed are thousands of small shield volcanoes, larger edifices up to several hundred kilometers in diameter, massive outpourings of lavas, and local pyroclastic deposits. Although most features are consistent with basaltic compositions, a number of large pancake-like domes are morphologically similar to rhyolite-dacite domes on Earth. Flows and sinuous channels with lengths of many hundreds of kilometers suggest that extremely high effusion rates or very fluid magmas (perhaps komatiites) may be present. Volcanism is evident in various tectonic settings (coronae, linear extensional and compressional zones, mountain belts, upland rises, highland plateaus, and tesserae). Volcanic resurfacing rates appear to be low (less than 2 Km(3)/yr) but the significance of dike formation and intrusions, and the mode of crustal formation and loss remain to be established.

Impact craters on venus: initial analysis from magellan.

Magellan radar images of 15 percent of the planet show 135 craters of probable impact origin. Craters more than 15 km across tend to contain central peaks, multiple central peaks, and peak rings. Many craters smaller than 15 km exhibit multiple floors or appear in clusters; these phenomena are attributed to atmospheric breakup of incoming meteoroids. Additionally, the atmosphere appears to have prevented the formation of primary impact craters smaller than about 3 km and produced a deficiency in the number of craters smaller than about 25 km across. Ejecta is found at greater distances than that predicted by simple ballistic emplacement, and the distal ends of some ejecta deposits are lobate. These characteristics may represent surface flows of material initially entrained in the atmosphere. Many craters are surrounded by zones of low radar albedo whose origin may have been deformation of the surface by the shock or pressure wave associated with the incoming meteoroid. Craters are absent from several large areas such as a 5 million square kilometer region around Sappho Patera, where the most likely explanation for the dearth of craters is volcanic resurfacing. There is apparently a spectrum of surface ages on Venus ranging approximately from 0 to 800 million years, and therefore Venus must be a geologically active planet.

Uranium-series dated authigenic carbonates and acheulian sites in southern egypt.

Field investigations in southern Egypt have yielded Acheulian artifacts in situ in authigenic carbonate deposits (CaCO(3)-cemented alluvium) along the edges of nowaggraded paleovalleys (Wadi Arid and Wadi Safsaf). Uranium-series dating of 25 carbonate samples from various localities as far apart as 70 kilometers indicates that widespread carbonate deposition occurred about 45, 141 and 212 ka (thousand years ago). Most of the carbonate appears to have been precipitated from groundwater, which suggests that these three episodes of deposition may be related to late Pleistocene humid climates that facilitated human settlement in this now hyperarid region. Carbonate cements from sediments containing Acheulian artifacts provide a minimum age of 212 ka for early occupation of the paleovalleys.

Shuttle imaging radar experiment.

The shuttle imaging radar (SIR-A) acquired images of a variety of the earth's geologic areas covering about 10 million square kilometers. Structural and geomorphic features such as faults, folds, outcrops, and dunes are clearly visible in both tropical and arid regions. The combination of SIR-A and Seasat images provides additional information about the surface physical properties: topography and roughness. Ocean features were also observed, including large internal waves in the Andaman Sea.

Subsurface valleys and geoarcheology of the eastern sahara revealed by shuttle radar.

The shuttle imaging radar (SIR-A) carried on the space shuttle Columbia in November 1981 penetrated the extremely dry Selima Sand Sheet, dunes, and drift sand of the eastern Sahara, revealing previously unknown buried valleys, geologic structures, and possible Stone Age occupation sites. Radar responses from bedrock and gravel surfaces beneath windblown sand several centimeters to possibly meters thick delineate sand- and alluvium-filled valleys, some nearly as wide as the Nile Valley and perhaps as old as middle Tertiary. The now-vanished major river systems that carved these large valleys probably accomplished most of the erosional stripping of this extraordinarily flat, hyperarid region. Underfit and incised dry wadis, many superimposed on the large valleys, represent erosion by intermittent running water, probably during Quaternary pluvials. Stone Age artifacts associated with soils in the alluvium suggest that areas near the wadis may have been sites of early human occupation. The presence of old drainage networks beneath the sand sheet provides a geologic explanation for the locations of many playas and present-day oases which have been centers of episodic human habitation. Radar penetration of dry sand and soils varies with the wavelength of the incident signals (24 centimeters for the SIR-A system), incidence angle, and the electrical properties of the materials, which are largely determined by moisture content. The calculated depth of radar penetration of dry sand and granules, based on laboratory measurements of the electrical properties of samples from the Selima Sand Sheet, is at least 5 meters. Recent (September 1982) field studies in Egypt verified SIR-A signal penetration depths of at least 1 meter in the Selima Sand Sheet and in drift sand and 2 or more meters in sand dunes.

Lunar regolith at tranquillity base.

The regolith at Tranquillity Base is a layer of fragmental debris that ranges in thickness from about 3 to 6 meters. The thickness of the regolith and the exposure histories of its constituent fragments can be related, by means of a relatively simple model, to the observed crater distribution.

Infrared scanning images: an archeological application.

Aerial infrared scanner images of an area near the Little Colorado River in north-central Arizona disclosed the existence of scattered clusters of parallel linear features in the ashfall area of Sunset Crater. The features are not obvious in conventional aerial photographs, and only one cluster could be recognized on the ground. Soil and pollen analyses reveal that they are prehistoric agricultural plots.