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PubMed1985

Sparteine oxidation polymorphism in Denmark.

Sparteine oxidation was polymorphic among 301 healthy Danish volunteers. Hence 22 subjects or 7.3% were phenotyped as poor metabolizers (PM) whereas 279 subjects were classified as extensive metabolizers (EM). The metabolic ratio (MR) between sparteine and 2- and 5-dehydrosparteine (% of dose) in 12 hrs urine ranged from 0.11-12.6 in EM and from 30-394 in PM. Urinary excretion of 2- and 5-dehydrosparteine also discriminated between PM and EM. Age, sex, and smoking habits did not influence the MR. This study confirms that sparteine is a useful probe drug in pharmacogenetic investigations.

Denmark↗
PubMed1983

The genetic control of sparteine and debrisoquine metabolism in man with new methods of analysing bimodal distributions.

Debrisoquine and sparteine tests were carried out in 215 random white British subjects. There is a high degree of correlation between the urinary 'metabolic ratios' of the two drugs. New mathematical techniques have been developed (1) to define phenotypes and (2) to identify the genotypes within the dominant phenotype. The members of 15 families were tested with both debrisoquine and sparteine. The results indicate that persons who are 'poor metabolisers' of sparteine are also 'poor metabolisers' of debrisoquine and are autosomal Mendelian recessives.

Adult↗
PubMed1982

In vitro metabolism of sparteine by human liver: competitive inhibition by debrisoquine.

Population data indicate that the genetic control is the same for the oxidation of sparteine and debrisoquine, although whether the level of control is regulatory or enzymatic is not clear. Therefore, the influence of debrisoquine on the rates of in vitro formation of the two dehydrogenated metabolites of sparteine in the 9000 x g supernatant fractions of human liver was examined. The interaction of these two drugs was competitive, indicating that the same form of cytochrome P450 is responsible for their biotransformation. Antipyrine at concentrations as high as 4 mM had no effect on sparteine oxidation.

Antipyrine↗
PubMed1989

[The excessive activity of cytochrome P450 system in ALS--the metabolic ratio of sparteine].

The activity of cytochrome P450 family was studied in patients with amyotrophic lateral sclerosis (ALS) in an attempt to evaluate the susceptibility to environmental substances including possible some neurotoxin. The metabolic ratio (MR) of sparteine sulfate was measured in 30 patients with ALS and 41 controls for the evaluation of the sparteine nitro (N)-oxidation with cytochrome P450 system. The population of phenotypes designed as extensive metabolisers (EMs), intermediate metabolisers (IMs), and poor metabolisers (PMs) for sparteine nitro (N)-oxidation was determined in each group. The lower MR (p less than 0.02) and higher frequency of EMs (p less than 0.05) were observed in ALS group, suggesting the excessive activity of N-oxidation with cytochrome P450 pathway in the ALS group. Especially in 15 patients with ALS age before 60, these tendencies were more remarkable with a significant lower MR (p less than 0.01) and extremely high frequency of EMs (p less than 0.005). The present study might suggest the possible participation of cytochrome P450 pathway in the development of ALS.

Adult↗
PubMedDate not supplied

In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase.

Human liver preparations were used to screen various drugs for their capability of binding to mephenytoin p-hydroxylase and sparteine monooxygenase, two cytochrome P-450-catalyzed activities that are independently heritable. For this screening, any indication of competitive inhibition by the drug was interpreted as an indication of binding. Among 64 drugs and alkaloids tested, 24 compounds caused inhibition of mephenytoin p-hydroxylation but the inhibition was weak in most cases; by contrast, 40 of the 64 compounds inhibited sparteine oxidation, the inhibition being potent in many cases. The only fairly strong inhibitors of mephenytoin p-hydroxylation were the alkaloid papaverine and the monoamine oxidase inhibitors tranylcypromine and nialamide. The results of these inhibition studies confirm the independence of the two monogenic defects observed in different populations. Metabolism is possibly altered in poor metabolizers of mephenytoin with fewer drugs than in poor metabolizers of sparteine.

Alkaloids↗
PubMed1994

Genetically determined sparteine oxidation polymorphism in a Polish population.

The genetic oxidation polymorphism was determined in 160 healthy Polish volunteers from the south-west of Poland (Wrocław region), using sparteine as a model drug. The results of a Polish population study revealed a bimodal distribution of the sparteine metabolic ratio and showed the existence of two oxidation phenotypes designated as extensive and poor metabolizers. The frequency of poor metabolizers in our study (8.8%) compares well with most results of poor oxidation metabolizers in Caucasian populations.

Adolescent↗
PubMed1979

Influence of the defective metabolism of sparteine on its pharmacokinetics.

Sparteine is metabolized by N1-oxidation, which in some subjects is defective. The defect has a pronounced effect on the kinetics of the drug. In nonmetabolisers elimination of sparteine proceeds entirely via renal excretion by a capacity-limited process, 99,9% of the dose being excreted as unchanged drug. In metabolisers the drug is mainly eliminated by metabolic degradation. Pronounced differences in beta-phase half-life and total plasma clearance were observed between metabolisers (156 min; 535 ml . min-1) and nonmetabolisers (409 min; 180 ml . min-1).

Adult↗
PubMed1980

Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine.

Two subjects from each of the three groups of homozygous rapid, heterozygous, and homozygous non-metabolizers (N-oxidation) of sparteine received a single oral dose of debrisoquine. The urinary ratio of debrisoquine/4-hydroxy-debrisoquine, reflecting the individual's capacity to C-hydroxylate debrisoquine, was closely related to his phenotype for sparteine metabolism. This indicates that the two metabolic reactions are controlled by similar if not identical genetic factors.

Adult↗
PubMed2001

Influence of CYP2D6 genotype and medication on the sparteine metabolic ratio of psychiatric patients.

OBJECTIVE: To investigate the influence of CYP2D6 genotype and medication on the reliability of phenotyping in a naturalistic setting of psychiatric inpatients. METHODS: The phenotype of 160 psychiatric inpatients was estimated by taking the urinary metabolic ratio (MR) of the concentrations of sparteine to 2- and 5-dehydrosparteine. Genotyping identified CYP2D6*1, *3, *4, *5 and *6 alleles as well as duplication of the CYP2D6 gene. All subjects underwent detailed drug history including drug dose and therapeutic drug monitoring to control compliance and abuse of other psychotropic drugs. These data were compared with those of 195 unmedicated healthy Germans. RESULTS: The cumulative distribution of the MR in patients showed a significant shift to higher MR when compared with that of healthy subjects (P < or = 0.001). Patients medicated either with selective serotonin reuptake inhibitors (SSRIs, P < or = 0.001), antipsychotic drugs (P= 0.002) or other drugs known to be substrates or inhibitors of CYP2D6 (P < or = 0.001) showed a significantly higher mean MR than unmedicated patients. However, there was no significant effect of tricyclic antidepressants on the MR. Healthy subjects with CYP2D6 deficiency were separated by a MR of greater than 20 from those who expressed functional CYP2D6. Seven patients carrying at least one functional CYP2D6 allele revealed a MR of greater than 20, indicating the occurrence of phenocopying. CONCLUSION: The results of phenotyping may be falsified by drugs known to be substrates or inhibitors of CYP2D6; thus, this method is not sufficiently reliable. However, since we observed the phenomenon of phenocopying only in patients treated with a SSRI such as fluoxetine, fluvoxamine or paroxetine, we conclude that sparteine phenotyping of medicated patients detects CYP2D6 deficiency correctly, provided that patients treated with these SSRIs are excluded.

Adult↗
PubMed1992

Gas chromatography/mass spectrometry assays for the determination of debrisoquine and sparteine metabolites in microsomal fractions of rat liver.

Debrisoquine and sparteine are prototype substrates of a genetic deficiency in cytochrome P450-dependent drug metabolism. Sensitive assays of in vitro oxidation of sparteine and debrisoquine are required for evaluation of this polymorphism. The activities were measured by quantitative analysis of 2-dehydrosparteine and 4-hydroxydebrisoquine production, respectively, using capillary column gas chromatography coupled with mass selective ion detection. With a single extraction, separation of parent drug, metabolite, and a suitable internal standard was readily achievable. Time-dependent production of both metabolites could be detected from as little as 40 micrograms of microsomal protein. Both activities showed a maximal activity with a 240-min incubation period. The ability to simultaneously quantify the parent drug and its metabolite suggests it would also be useful for evaluation of in vivo metabolism.

Animals↗
PubMed1982

Spectral binding studies of the polymorphically metabolized drugs debrisoquine, sparteine and phenformin by cytochrome P-450 of normal and hydroxylation deficient rat strains.

The mechanisms of polymorphic drug hydroxylation of debrisoquine, sparteine and related drugs in vivo have been investigated using Cyt P-450 preparations of inbred rat strains as an in vitro model of the poor and extensive metabolizer phenotypes found in various rat strains and in man. Optical difference spectroscopy with debrisoquine, sparteine, phenformin and three other drugs (selected test compounds with proven or suspected hydroxylation polymorphisms in man) exhibited Type 1 binding in normal Sprague-Dawley, Fischer and Lewis Cyt P-450, whereas no Type I drug binding was found in the hydroxylation deficient DA rat liver Cyt P-450. Cyt P-450 content and Type II drug binding of metiamide was the same in normal and hydroxylation deficient rat liver microsomes. The pronounced Type I drug binding in extensive hydroxylation Cyt P-450 and the defective Type I binding in DA Cyt P-450 in vitro, therefore, closely parallels the polymorphic hydroxylation pattern of these test drugs found in the four rat strains studied in vivo. Consequently, missing binding properties of Cyt P-450 or of its micro-environment might represent the enzymatic defect underlying the genetically determined hydroxylation deficiency of polymorphically metabolized drugs in the poor metabolizer phenotype in the DA rat and, by inference, in man.

Animals↗
PubMed1985

Benzo(a)pyrene metabolism in hepatic microsomes from female DA rats with a genetic sparteine oxidation deficiency.

The impact of the genetic hydroxylation deficiency described for several drugs such as sparteine, debrisoquine, and phenformin, has been studied with respect to benzo(a)pyrene (BP) metabolite formation. 14C-BP (80 microM) was incubated with liver microsomes from female DA rats deficient in sparteine oxidation; microsomes from female Sprague-Dawley rats served as controls. BP metabolites were separated by high pressure liquid chromatography (HPLC). No significant differences were detected in the overall formation rate of 9,10-,4,5-, and 7,8-dihydrodiol-BP, of 4 quinones, or of 9-OH- and 3-OH-BP. Thus, the study suggested no association between genetic hydroxylation polymorphism (debrisoquine/sparteine type) and the formation of at least 6 BP metabolites.

Animals↗
PubMed2002

A readily-accessible (+)-sparteine surrogate.

A "(+)-sparteine-like" chiral diamine, readily synthesized in three steps from (-)-cytisine, has been evaluated in four different asymmetric transformations; in each case, selectivity in an enantiocomplementary fashion to (-)-sparteine was observed.

Alkaloids↗
PubMed2004

A computational model relating structure and reactivity in enantioselective oxidations of secondary alcohols by (-)-sparteine-Pd(II) complexes.

The key interactions responsible for the unique reactivity of (-)-sparteine-PdX(2) complexes (X = chloride, acetate) in the enantioselective oxidation of secondary alcohols have been elucidated using quantum mechanics (B3LYP DFT with the PBF polarizable continuum solvent model). From examining many possible pathways, we find the mechanism involves: (1) substitution of the alcohol in place of an X-group, (2) deprotonation of the bound alcohol by the deposed anion and free sparteine, (3) beta-hydride elimination through a four-coordinate transition state in which the second anion is displaced but tightly associated, (4) replacement of the ketone product with the associated anion. The enantioselectivities observed under base-rich reaction conditions follow directly from calculated energies of diastereomeric beta-hydride elimination transition states incorporating (R) and (S) substrates. This relationship reveals an important role of the anion, namely to communicate the steric interaction of the ligand on one side of the Pd(II) square plane and the substrate on the other side. When no anion is included, no enantioselectivity is predicted. Locating these transition states in different solvents shows that higher dielectrics stabilize the charge separation between the anion and metal and draw the anion farther into solution. Thus, the solvent influences the barrier height (rate) and selectivity of the oxidation.

Alcohols↗
PubMed2004

Is the A-ring of sparteine essential for high enantioselectivity in the asymmetric lithiation-substitution of N-Boc-pyrrolidine?

The simplest chiral portion of sparteine, N,N'-dimethyl-2-endo-methylbispidine, was prepared and evaluated in the asymmetric lithiation-substitution of N-Boc-pyrrolidine. The results indicate that the complete A-ring of sparteine is essential for high levels of asymmetric induction. DFT-QSSR analyses of the diamine/Li(+) complexes and DFT calculations of the pertinent i-PrLi/diamine/N-Boc-pyrrolidine complexes are predictive and provide complementary pictures of the stereochemical features critical to this transformation.

Diamines↗
PubMed2001

Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.

Magnetic Resonance Spectroscopy↗
PubMed2001

Synthesis of enantiomerically enriched allenes by (-)-sparteine-mediated lithiation of alkynyl carbamates.

[reaction: see text]. The alpha-deprotonation of alkynyl carbamates 3 with the chiral base (-)-sparteine (4)/n-butyllithium, transmetalation with ClTi(O(i)()Pr)3, and subsequent substitution with an aldehyde results in the formation of enantioenriched 4-hydroxyallenyl carbamates 11. Stereoselection is determined by dynamic resolution of the lithium/(-)-sparteine complexes by selective crystallization.

Aldehydes↗
PubMed1980

Deficient metabolism of debrisoquine and sparteine.

Genetic deficiencies of alicyclic hydroxylation of debrisoquine and of sparteine oxidation are independently discovered entities, each of clinical significance in its sphere. This paper reports evidence to indicate that these 2 deficiencies have the same cause. Previous investigation of one of the affected subjects had revealed normal oxidative metabolism of amobarbital and antipyrine in terms of both metabolic rates and urinary metabolite patterns. Thus the genetic defect in the metabolism of sparteine and debrisoquine is not a generalized deficiency of drug oxidation or of the cytochrome P450 system.

Amobarbital↗