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PubMed1982

Sparteine metabolism in Canadian Caucasians.

The capacity for sparteine (SP) metabolism was determined in 48 Caucasian subjects by measuring amounts of drug and dehydrogenated metabolites in urine after an oral dose of SP sulfate. Three phenotypes were recognized and were assumed to represent individuals homozygous for poor SP oxidation (group III) and those heterozygous (group II) and homozygous (group I) for extensive SP oxidation. Separation of groups I and II, although incomplete, was improved by alterations in the published analytic procedure. The pattern of deviations from the normal distribution was similar for both dehydrosparteine metabolites. This supports the hypothesis of a common intermediate, the formation of which is monogenically controlled. Correlation analysis of the two metabolites indicates the possibility of further metabolism of 5-dehydrosparteine.

Canada↗
PubMed1988

First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype.

Four rapid extensive metabolizers (EM), four slow EM, and three poor metabolizers (PM) of sparteine were given single intravenous doses of 50 mg imipramine and desipramine. All subjects had previously taken single oral doses (100 mg) of imipramine and desipramine. The first-pass metabolism of imipramine and desipramine ranged from 23% to 73% and 0% to 48%, respectively, and was more pronounced for both drugs in EM than in poor metabolizers. The study suggested saturable 2-hydroxylation of imipramine and desipramine during the first-pass through the liver, especially in EM.

Adult↗
PubMed1988

The oxidative metabolism of sparteine in the Cuna Amerindians of Panama: absence of evidence for deficient metabolizers.

Sparteine sulfate (50 mg) was administered to 170 Cuna Amerindians, 142 of whom were unrelated, and the drug and its dehydrometabolites were determined in the 0- to 12-hour urine samples. The log10 of the metabolic ratio was unimodally, but not normally, distributed and showed the following values: mean -0.21 +/- 0.26, median -0.24, limits -0.73 and 0.76, skewness 1.00, and kurtosis 4.95. On the basis of these results, it can be concluded that there are no deficient metabolizers in the Cuna sample population studied. However, the similarity of the skewness found between the Cuna sample population studied and the extensive Canadian white group, as well as an inflection point at 6.3 U in the former's probit plot, suggests the existence of at least two subgroups congregating within the same single mode in the frequency distribution curve. The use of the inflection point is discussed thoroughly, concluding that although it does not allow exclusion of the existence of genotypically different subgroups, the limitations of the data do not permit its use to determine the number of heterozygotes and thus the existence of polymorphism. The possibility of an isozyme variant, consistent with the general genetic structure of Amerindians, as suggested by the coexistence of two subgroups within the unimodal curve, is entertained.

Adolescent↗
PubMed2004

Concise asymmetric synthesis of (-)-sparteine.

A six-step asymmetric synthesis of natural (-)-sparteine from ethyl 7-iodohept-2-enoate is reported, involving a connective Michael addition of an amino ester-derived enolate to an alpha,beta-unsaturated amino ester.

Amino Acids↗
PubMed2004

A synthesis of (+/-)-sparteine.

(+/-)-Sparteine has been synthesised with stereochemistry controlled in such a way as to make the route amenable to an efficient synthesis of either enantiomer.

Molecular Structure↗
PubMed1991

Identification of a novel CYP2D6 allele associated with poor metabolism of sparteine in a Japanese population.

The relationship between genotypes associated with restriction fragment length polymorphisms at the P450 CYP2D locus and the metabolic phenotypes for sparteine in healthy Japanese subjects was investigated. Four distinct restriction fragments of 44 kb, 29 kb, 11.5 kb or 16 + 9 kb after digestion with Xba I were observed. The genotype of Xba I 11.5 kb, which is predictive of the poor metabolizer phenotype in Caucasians is also associated with Japanese poor metabolizers. Most Xba I 44 kb are associated with the extensive metabolizer phenotype. However, one Xba I 44 kb haplotype in linkage disequilibrium with a Bam HI restriction fragment length polymorphism allele, designated Bam HI 2.3 kb-, appears to be a novel mutant CYP2D6 allele in Japanese subjects having the poor metabolizer phenotype.

Adolescent↗
PubMed2003

Bis(azido-kappaN)[(6R,7S,8S,14S)-(-)-sparteine-kappa2N,N']copper(II).

In the title compound, [Cu(N(3))(2)(C(15)H(26)N(2))], the chiral alkaloid (-)-l-sparteine (Sp) acts as a bidentate ligand, with two azide ligands occupying the remaining coordination sites, forming a distorted CuN(4) tetrahedron. The dihedral angle between the N(Sp)-Cu-N(Sp) and N(azide)-Cu-N(azide) planes is 55.3 (2) degrees. Principal dimensions include Cu-N(Sp) = 2.011 (6) and 2.025 (5) A, and Cu-N(azide) = 1.939 (6) and 1.934 (7) A. The mid-point of the N(Sp)...N(Sp) line does not lie exactly in the N(azide)-Cu-N(azide) plane, but is tilted towards one of the N(Sp) atoms by 0.026 A.

Crystallography, X-Ray↗
PubMed1980

Segregation of leech neurones by the effect of sparteine on action potential duration.

1. Sparteine (SPT) and 3- or 4-aminopyridine, were applied to leech segmental ganglia and the electrophysiological responses of the Retzius (R) and sensory neurones responding to pressure (P), touch (T), and noxious (N) stimuli analysed. 2. SPT 0.05-0.5 mM when presented via the bath to the whole ganglion prolonged the action potentials of these neurones to characteristically different degrees; the cells were clearly segregated in the order R greater than N greater than P greater than T at 0.5 mM, regardless of exposure time. 3. The plateau of the prolonged action potentials in the R and N cells was sustained by either Ca or Sr and was blocked by Mn, in normal or Na-free Ringer. These responses were similar to those seen in the same cell types with TEA under the same condition. 4. The SPT prolongation of action potentials was favoured by alkalinization of the Ringer solution. This implies that the drug acted in its uncharged form. SPT was ineffective when applied by pressure into the somata of these four neurones. This may be because SPT was charged at the intracellular pH or because it acted at some external membrane site. 5. The aminopyridines when applied in the bath had no effect on the repolarization of these four neurones. 6. These results suggest that TEA and SPT probably act on repolarization by similar mechanisms. The parameter of membrane function principally affected is probably a K current which contributes to repolarization to different degrees in the four cells and which may be activated by Ca.

Action Potentials↗
PubMed1988

Further analysis of sparteine oxidation in a Japanese population and comparison with data observed in different ethnic populations.

1. Data on the oxidation polymorphism of sparteine (SP) studied in 84 unrelated Japanese subjects of whom two (2.4%) were classified as poor metabolizers (PMs) were re-evaluated. The data were obtained from 6-hour urinary excretion ratios of SP to 2- and 5-dehydrosparteines (DHS), after an oral dose of 100 mg of SP sulphate. 2. Urinary excretion of both SP and DHS correlated with the SP/DHS ratio (rs = 0.862 and -0.756, respectively, P less than 0.001). In addition, urinary excretion of 2-DHS, 5-DHS or total DHS discriminated between PMs and extensive metabolizers (EMs). There was also a highly significant correlation (rs = 0.669, P less than 0.001) between the urinary excretion of 2- and 5-DHS. 3. These re-evaluated results on the oxidation polymorphism of SP indicate that 2- and 5-DHS formation from SP shares a common metabolic pathway (presumably via the same P-450 isozyme), and that the SP/DHS ratio, conventionally used as a discriminating index between PMs and EMs, quantitatively reflects the capacity of 2- and 5-DHS formation. 4. The benefit of using a shorter (6 h) collection period for assessing the individual oxidation phenotype of SP and inter-ethnic comparison of SP oxidation is also discussed.

Adult↗
PubMed1998

Ultrarapid metabolism of sparteine: frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction.

CYP2D6 is a polymorphically expressed enzyme with two phenotypes. Poor metabolizers lack the enzyme caused by inactivating mutations in the CYP2D6 gene and extensive metabolizers have at least one active CYP2D6 gene. Extensive metabolizers with very high capacity for CYP2D6 dependent drug metabolisms are termed ultrarapid metabolizers and carry alleles with duplicated, multi duplicated or amplified CYP2D6 genes. In the present study, we examined the frequency of CYP2D6 gene duplications in a Danish population and validated a long polymerase chain reaction method for identification of ultrarapid metabolizers. Sixty individuals having a metabolic ratio for sparteine at or below 0.15 were selected and a control group of 53 individuals with a metabolic ratio between 0.16 and 12.4 was used. Based on EcoRI restriction fragment length polymorphism analysis, eight individuals were found with a duplicated CYP2D6 gene, whereas using a long polymerase chain reaction method, nine individuals with a 3.6 kb fragment indicative of two CYP2D6 genes in tandem were found among the 60 individuals with a low metabolic ratio. No gene duplication was found in the control group or in any individuals with a metabolic ratio > 0.14. Based on these results, we estimate the frequency of individuals with CYP2D6 duplication in the Danish population to be 0.8%, which is comparable to the frequency in the Swedish and the German populations, but considerably lower than in Spanish or African populations. We conclude that the long polymerase chain reaction assay is simple and reliable for detection of duplications of the CYP2D6 gene.

Alleles↗
PubMed1986

Non-linear pharmacokinetics of sparteine in the rat.

In rats, blood concentrations of sparteine (SP) and relative concentrations of sodium borohydride-reducible metabolite following intra-arterial (i.a.) and portal venous administration of SP-sulphate were estimated up to 200 min. In 24 hr urine, unchanged SP was quantitated. Borohydride-reducible metabolite was measured as the difference in SP concentrations before and after reduction. Administration of SP in a dose of 50 mg/kg SP-sulphate i.a. revealed a blood concentration-time profile which did not allow characterization of the terminal half-life or systemic clearance. Therefore, the dose over the area under the curve up to 120 min after administration, CL0-120app, was defined as an apparent average clearance value over the time interval studied. After a dose of 50 mg/kg the CL0-120app was 34.8 +/- 5.9 ml/min/kg when administered i.a. and 80.4 +/- 7.5 ml/min/kg when administered via the portal vein, thus affording an estimate of 0.64 +/- 0.12 for the hepatic extraction ratio. A possible biliary excretion and enterohepatic circulation was studied in rats with a bile fistula. Although SP levels in blood were lower than in control rats, no SP was excreted in the bile and excretion of SP in urine was even slightly higher, which renders circulation of SP itself unlikely. About 25% of the dose was recovered in 180 min bile as borohydride-reducible metabolite, but the urinary excretion of borohydride-reducible metabolite was not changed. The gradual levelling-off of blood concentration versus time curves may partly be explained by the formation of reactive intermediates in the course of metabolism, which inactivate P-450. In support of this, the intrinsic clearance of orally administered hexobarbital (25 mg/kg) was determined 5 and 50 min after i.a. administered SP-sulphate (50 mg/kg), and decreased from 343 +/- 18 to 220 +/- 36 ml/min/kg (p less than 0.05).

Animals↗
PubMed1993

[Insufficient effect of nortriptyline in a rapid metabolizer of sparteine].

A 61-year old woman suffering from depression was treated with 150 mg nortriptyline daily for eight weeks by her general practitioner. In spite of this dose, her S-nortriptyline was only 100 nmol/1 (recommended range: 225-600 nmol/1), and she remained depressed and was admitted to hospital. A sparteine test gave a metabolic ratio of 0.06, hence the patient was classified as a very rapid extensive metabolizer. Her nortriptyline dose was increased to 250 mg/day and the S-nortriptyline rose to 528 nmol/l. After eight weeks of sufficient nortriptyline treatment, the patient was still depressed. The patient recovered completely after a series of five electroconvulsive treatments.

Female↗
PubMed1997

(+)-Sparteine N-16-oxide, a lupin alkaloid from Lygos raetam var. sarcocarpa.

A new lupin alkaloid, (+)-sparteine N-16-oxide was isolated from Lygos raetam var. sarcocarpa, together with five known alkaloids: (+)-aphylline, (+)-17 oxosparteine, (-)-5,6-dehydrolupanine, (-)-N-formyl cytisine and (+)-ammodenderine. The structure of the new alkaloid including absolute configuration was determined by spectroscopic methods and chemical transformation.

Alkaloids↗
PubMed2004

Mass spectrometry of bisquinolizidine alkaloids: 2- and 17-cyano-substituted derivatives of sparteine and lupanine.

The mass spectral fragmentations of 2-cyano-2-methylsparteine (1), 2-cyano-2-phenylsparteine (2), 2-cyano-2-(p-tolyl)sparteine (3), 17-cyanosparteine (4) and 17-cyanolupanine (5) were investigated. Fragmentation pathways, whose identification was assisted by accurate mass measurements and a correlation between the abundances of the M(+*) and the selected fragment ions of the investigated compounds, are discussed. The data obtained create the basis for distinguishing the structural metamers.

Journal Article↗
PubMed2004

An experimentally derived model for stereoselectivity in the aerobic oxidative kinetic resolution of secondary alcohols by (sparteine)PdCl2.

A model for asymmetric induction in palladium-catalyzed aerobic oxidative kinetic resolution is described. The model is based on coordination complexes and general reactivity trends of the parent (sp)PdCl2 catalyst. The first example of a nonracemic chiral palladium alkoxide complex is presented, and exhibits the subtle steric influences of the C1 symmetric ligand sparteine.

Journal Article↗
PubMed2000

Atropisomeric amides as chiral ligands: using (-)-sparteine-directed enantioselective silylation to control the conformation of a stereogenic axis

An enantiomerically pure (1-trimethylsilyl)ethyl group, constructed by a (-)-sparteine-directed enantioselective quench of a laterally lithiated tertiary aromatic amide, exerts powerful thermodynamic control over the conformation of the adjacent tertiary amide substituent. Ortholithiation and functionalization of the amide in the 6-position allows the single amide conformer to be trapped as an enantiomerically and diastereoisomerically pure amide atropisomer. Protodesilylation of the amide gives functionalized atropisomeric amides with a stereogenic axis of single absolute configuration, whose barriers to racemization have been determined by polarimetry. Enantiomerically pure amides bearing phosphine substituents are effective ligands in a Pd-catalyzed allylic substitution reaction-the first use of a nonbiaryl atropisomer as a chiral ligand-and give products with 90% ee. The rate of racemization of the phosphine-substituted amide is powerfully influenced by the presence of palladium.

Journal Article↗