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1

Electronic Resource

Interconversion between haloperidol and reduced haloperidol in healthy volunteers (1989)

Chakraborty, B. S. ; Hubbard, J. W. ; Hawes, E. M. ; [et al.]

Springer

European journal of clinical pharmacology 37 (1989), S. 45-48

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ISSN: 1432-1041

Keywords: haloperidol (HAL) ; reduced haloperidol (RHAL) ; interconversion

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary The interconversion between haloperidol (HAL) and reduced haloperidol (RHAL) was examined following their separate administration in low (5 mg) single oral doses to 15 young healthy male volunteers in a crossover design. Using an ultrasensitive HPLC method plasma concentrations of HAL and RHAL were monitored over a period of one week following each administration. Except in one case, both the analytes were found in the plasma of all the volunteers following each administration, thereby indicating interconversion of the two compounds. Comparison of the AUC(0-t) ratios of RHAL/HAL and HAL/RHAL following administration of HAL and RHAL, respectively, revealed that the interconversion favours the reduction of HAL to RHAL. The disposition of HAL following administration of RHAL appears to be limited by its rate of formation and the disposition of RHAL following administration of HAL, on the other hand, is much slower than that of the parent compound.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00609423

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2

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Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine (1996)

Muralidharan, G. ; Cooper, J. K. ; Hawes, E. M. ; [et al.]

Springer

European journal of clinical pharmacology 50 (1996), S. 121-128

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ISSN: 1432-1041

Keywords: Key words Chlorpromazine ; CYP2D6; 7-hydroxychlorpromazine ; quinidine ; polymorphic metabolism

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Quinidine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48 h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethylmethoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (r s = −0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethylchlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (α = 0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050079

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3

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Stereoselective pharmacokinetics of doxepin isomers (1992)

Midha, K. K. ; Hubbard, J. W. ; McKay, G. ; [et al.]

Springer

European journal of clinical pharmacology 42 (1992), S. 539-544

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ISSN: 1432-1041

Keywords: Doxepin ; N-desmethyldoxepin ; stereoselective pharmacokinetics ; stereoselective metabolism ; Cis isomer ; trans isomer

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary Commercial preparations of the tricyclic antidepressant doxepin contain 15% of the more active cisdoxepin and 85% of the trans-isomer. The single dose pharmacokinetics of doxepin and its major metabolite N-desmethyldoxepin were examined in 30 healthy young men. Results for total doxepin showed wide intersubject variation in all pharmacokinetic parameters except tmax and Cmax. Plasma levels of cis-doxepin were extremely low and it was only possible to estimate the stereoselective pharmacokinetics of the parent drug in 3 subjects. The data from those particular subjects resulted in an average ratio of cis- to trans-doxepin isomers in plasma of 15:85. In contrast, the mean plasma levels of cis-N-desmethyldoxepin in 28 subjects exceeded those of the trans-isomer at every time point after 10 h, such that the areas under the plasma concentration versus time curves (AUC) of cis-N-desmethyldoxepin were significantly higher than those of the corresponding trans-isomer. This phenomenon may play an important role in the therapeutic action of doxepin since it has been suggested that cis-N-desmethyldoxepin is pharmacologically active. In 2 subjects, however, the AUC 0-inf of trans-N-desmethyldoxepin were respectively 4 and 8 fold higher than those of the cis-isomer.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00314865

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4

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The arrangement of resources in patchy landscapes: effects on distribution, survival, and resource acquisition of chironomids (2000)

Silver, P. ; Cooper, J. K. ; Palmer, M. A. ; [et al.]

Springer

Oecologia 124 (2000), S. 216-224

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ISSN: 1432-1939

Keywords: Key words Landscape ecology ; Chironomus riparius ; Density dependence ; Resource patch arrangement ; Life history

Source: Springer Online Journal Archives 1860-2000

Topics: Biology

Notes: Abstract The spatial arrangement of resources in patchy habitats influences the distribution of individuals and their ability to acquire resources. We used Chironomus riparius, a ubiquitous aquatic insect that uses leaf particles as an important resource, to ask how the dispersion of resource patches influences the distribution and resource acquisition of mobile individuals in patchy landscapes. Two experiments were conducted in replicated laboratory landscapes (38×38 cm) created by arranging sand and leaf patches in a 5×5 grid so that the leaf patches were either aggregated or uniformly dispersed in the grid. One-day-old C. riparius larvae were introduced into the landscapes in one of three densities (low, medium, high). In experiment 1, we sampled larvae and pupae by coring each patch in each landscape 3, 6, 12, or 24 days after adding larvae. In experiment 2, emerging adults were collected daily for 42 days from each patch in each landscape. In aggregated landscapes, individuals were aggregated in one patch type or the other during a particular developmental stage, but the ”preferred” type changed depending on developmental stage and initial density. Adult emergence was lower by about 30% in all aggregated landscapes. In dispersed landscapes, individuals used both types of patch throughout their life cycles at all initial densities. Thus, patch arrangement influences the distribution of mobile individuals in landscapes, and it influences resource acquisition even when average resource abundance is identical among landscapes. Regardless of patch arrangement, high initial density caused accumulation of early instars in edge patches, 75% mortality of early instars, a 25% increase in development time, and a 60% reduction in adult emergence. Because mortality was extremely high among early-instar larvae in high-density treatments, we do not have direct evidence that the mechanism by which patch arrangement operates is density dependent. However, the results of our experiments strongly suggest that dispersion of resource patches across a landscape reduces local densities by making non-resource patches available for use, thereby reducing intraspecific competition.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s004420050009

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5

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The elucidation of the mass spectral fragmentation pathway of α-methyldopamine derivatives by chlorine labelingTFA = trifluoroacetyl; TFAA = trifluoroacetic anhydride; CFAA = monochlorodifluoroacetic anhydride. (1979)

Hubbard, J. W. ; Midha, K. K. ; Cooper, J. K. ; [et al.]

Chichester : Wiley-Blackwell

Biological Mass Spectrometry 6 (1979), S. 554-558

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ISSN: 0306-042X

Keywords: Chemistry ; Analytical Chemistry and Spectroscopy

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: The mass spectra of the tristrifluoroacetyl derivative of α-methyldopamine and the bistrifluoroacetyl derivative of 3-O-methyl-α-methyldopamine contain important ions which can be rationalized by two alternative fragmentation pathways. These ambiguities were resolved by means of a simple chemical derivatization technique. The labile phenolic ester groups were hydrolyzed and subsequently re-esterified by reaction with chlorodifluoroacetic anhydride in the presence of ethyl acetate thereby labeling ions containing ester group(s) in the mass spectra with the diagnostic chlorine isotope ratio. This resulted in the addition of 16/18 mass units to the weights of the ions for each fluorine atom replaced by chlorine. Since it was easy to distinguish loss of the mass of a neutral molecule of trifluoroacetamide (113 mass units) from the ions of a chlorodifluoroacetoxy radical (129 mass units), the elimination of trifluoroacetamide was distinguished from that of trifluoroacetoxy radical. Derivatives were also prepared in which the chlorine label was located on the N-acyl function. The mass spectra of the chlorine labeled compounds showed that the major fragmentation pathway of tristrihaloacetyl-α-methyldopamine and bistrihaloacyl-3-O-methyl-α-methyldopamine is by loss of a neutral molecule of trihaloacetamide.

Additional Material: 2 Tab.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/bms.1200061204

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6

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A gas chromatographic mass spectrometric assay for plasma trifluoperazine concentrations following single doses (1982)

Midha, K. K. ; Roscoe, R. M. H. ; Hall, K. ; [et al.]

Chichester : Wiley-Blackwell

Biological Mass Spectrometry 9 (1982), S. 186-190

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ISSN: 0306-042X

Keywords: Chemistry ; Analytical Chemistry and Spectroscopy

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: A gas chromatographic mass spectrometric assay using selected ion monitoring is described which permits the determination of trifluoperazine in plasma at concentrations ranging from 0.078 to 5.0 ng ml-1. It relies on the extraction of trifluoperazine and the internal standard, prochlorperazine or the tetradeuterated analogue of trifluoperazine, form basified plasma with a n-pentane/2-propanol solvent mixture. Following the evaporation of organic solvent, the residue is reconstituted in a small volume of methanol. Suitable aliquots were anlysed by the combined technique of gas chromatography/electron impact mass spectrometry with a data system. The described procedure is specific and enables the quantitation of 78 pg ml-1 of the drug with a coefficient of variation 〈7%. The method has demonstrated sufficient sensitivity to permit pharmacokinetic and bioavailability studies after a single 5 mg oral dose.

Additional Material: 3 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/bms.1200090503

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