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At least 127 records · Page 7Linked to original sources
PubMed1994

S-mephenytoin, sparteine and debrisoquine oxidation: genetic polymorphisms in a Turkish population.

A mephenytoin test was carried out in 106 unrelated healthy Turkish volunteers. Racemic mephenytoin was coadministered with either debrisoquine or sparteine. The S/R mephenytoin ratio ranged from < 0.1 to 0.73 in 105 subjects, accordingly phenotyped as extensive metabolisers. One subject had an S/R mephenytoin ratio of 1.02, showing that he was a poor metaboliser of mephenytoin (0.94%, confidence interval 0.25% and 13.65%). In 48 subjects, the metabolic ratios of debrisoquine and sparteine were correlated significantly (rs = 0.61, P < 0.001).

Adolescent↗
PubMed1995

Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms--a population study.

1. Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks later each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by h.p.l.c. 2. The medians of the hydroxylation ratios (i.e. 2-hydroxy-metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EMs) as compared with 27 poor metabolizers (PMs), but none of the ratios separated the two phenotypes completely. 3. There were 324 EM of mephenytoin (EMM) and three PM (PMM) in the sample. The demethylation ratios between desipramine, 2-hydroxy-desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman's rs: -0.20 and -0.27, P < 0.05). 4. The demethylation ratios were higher in 80 smokers than in 245 non-smokers. This indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N-demethylation of imipramine. 5. CYP2D6 genotyping was carried out by PCR in 325 of the subjects, and the D6-wt allele was amplified in 298 EMs, meaning that they were genotyped correctly. One PMs was D6-wt/D6-B, another PMs had the genotype D6-wt/ and hence both were misclassified as EMs. The remaining 25 PMs were D6-A/D6-B (n = 5), D6-B/ (n = 18) or D6-D/D6-D (no PCR amplification, n = 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Amantadine and sparteine inhibit ATP-regulated K-currents in the insulin-secreting beta-cell line, HIT-T15.

1. The effects of pharmacological agents that potentiate insulin release were studied on ATP-regulated K-currents (K-ATP currents) in the insulin-secreting beta-cell line HIT-T15 by use of patch-clamp methods. 2. The tricyclic drug, 1-adamantanamine (amantadine), reversibly inhibited both whole-cell currents (with a Ki of 120 microM) and single channel currents in inside-out patches. This effect was principally due to an increase in a long closed state which reduced the channel open probability. The related compound, 1-adamantanol, in which the amino group is substituted by a hydroxyl one, did not inhibit K-ATP currents substantially. 3. The alkaloid, sparteine, reversibly inhibited both whole-cell K-ATP currents (Ki = 171 microM) and single channel currents in inside-out patches. 4. The results suggest that sparteine and amantadine can block the K-ATP channel from either side of the membrane and support the idea that at least part of the stimulatory effect of these agents on insulin secretion results from inhibition of this channel.

Adenosine Triphosphate↗
PubMed1986

The relationship between the acetylator and the sparteine hydroxylation polymorphisms.

Thirty-eight healthy white British Caucasian subjects were hydroxylator phenotyped with sparteine and acetylator phenotyped with sulphadimidine. The results showed that there was no significant difference in the mean sparteine metabolic ratio between eight rapid acetylator extensive hydroxylators and 27 slow acetylator extensive hydroxylators.

Acetylation↗
PubMed1984

A human cytochrome P-450 characterized by inhibition studies as the sparteine-debrisoquine monooxygenase.

The present study compares the debrisoquine monooxygenase and the sparteine monooxygenase activities of human liver microsomes. In the presence of 14 competitive inhibitors, apparent inhibition constants (Ki) as determined by these two activities ranged over four orders of magnitude with a correlation coefficient 0.99. These in vitro results represent the strongest evidence to date that the debrisoquine monooxygenase and the sparteine monooxygenase are identical and involve a single isozyme of cytochrome P-450.

Cytochrome P-450 CYP2D6↗
PubMed1991

Absence of polymorphism of sparteine oxidation in the South African Venda.

1 This study has found no occurrence of poor metabolism of sparteine within a South African Venda population of 97 subjects. 2 On the basis of MR (metabolic ratio) the mean and distribution of the results are very similar to those found in Ghanaians. 3 The distribution is also similar to that for fast metabolizers in Caucasians. 4 It is concluded that different P450 cytochromes are responsible for immediate oxidation of debrisoquine and sparteine, but that both may be activated by the same P450 reductase.

Adult↗
PubMed1996

Sparteine metabolism in a Nigerian population.

The oxidative metabolism of sparteine has been investigated in a Nigerian population. The distribution of metabolic capacities was shown to be skewed with two subjects (2/97, 2.1%) being relatively deficient in their ability to produce the dehydrometabolites. These observations afford evidence that sparteine oxidation is under polymorphic control in Nigerians.

Adult↗
PubMed1989

Effect of sparteine and quinidine on the metabolism of methoxyphenamine by Cunninghamella bainieri.

1. The fungus C. bainieri, incubated for 7 days with methoxyphenamine alone or in combination with either sparteine or quinidine, gave N-desmethylmethoxyphenamine and its N-acetyl conjugate as major metabolites, while O-desmethylmethoxyphenamine, 5-hydroxymethoxyphenamine and 2-hydroxyamphetamine were produced in lesser amounts. In addition, 1-(2-hydroxyphenyl)-2-aminopropane, 1-hydroxy-1-(2-methoxyphenyl)-2-propanone, beta-hydroxymethoxyphenamine, and 1-(5-hydroxy-2-methoxyphenyl)-2-aminopropane were tentatively identified as minor components of the fungal biotransformation of methoxyphenamine. 2. As observed in mammalian systems, the addition of either sparteine or quinidine decreased the rate and extent of methoxyphenamine biotransformation. 3. C. bainieri may be a useful model for drug interaction studies.

Biotransformation↗
PubMed1992

[Sparteine and tedisamil inhibit chloride channels in pulmonary epithelial cells isolated from patients with cystic fibrosis].

Chloride current was measured in cells isolated from the pulmonary epithelium of patients with cystic fibrosis. By applying the whole cell patch clamp method three types of chloride current were identified, i.e. a time-dependent, an activating with time, and an inactivating with time. The time-dependent component of ICl proved to be DIDS sensitive. The effect of the potassium current blocker sparteine and its analogue tedisamil on ICl was tested. both substances were found to be chloride current inhibitors, yet the effectiveness of sparteine was 10(4) times higher.

Bridged Bicyclo Compounds↗
PubMed1991

[Severe nortriptyline poisoning in poor metabolizers of the sparteine type].

Approximately 7% of the Danish population are so called poor metabolizers (PM) as regards the model compound sparteine. These individuals lack the P450 isozyme which is mainly responsible for elimination of at least 20 different medicaments including nortriptyline. A woman aged 42 years suffering from depression was treated with 100 mg nortriptyline daily and, during the course of treatment, she developed a toxic serum nortriptyline level (approximately 2,100 nM). Treatment was withdrawn temporarily on account of severe side-effects. The depression recurred. During the medicine-free period, a sparteine test was performed and this demonstrated that the patient was a poor metabolizer. Scarcely two months after hospitalization, treatment was recommenced with 25 mg nortriptyline daily after which the patient's depression disappeared completely without any side-effects of note.

Adult↗
PubMed1989

A fatal ingestion of sparteine and meprobamate: medicolegal and toxicological data.

A case of suicidal overdose from the ingestion of Palpipax (meprobamate and sparteine) is presented. The drugs were quantified in biological fluids and tissues using gas chromatography. The blood concentrations of meprobamate and sparteine were found to be 88.2 and 40.4 micrograms/ml, respectively. Results are discussed in the light of the existing literature.

Acute Disease↗
PubMed1989

[A susceptible factor to acquire parkinsonism: sparteine oxidation polymorphism].

Recently, we found that hepatic oxidative enzyme(s) functions to attenuate neurotoxic effects of MPTP by converting the agent to its inactive metabolite(s) and reducing the amount of MPTP reaching at the brain in mice. Since the factors affecting the neurotoxic effects of MPTP may be related to the cause of spontaneous Parkinsonism, we studied the oxidation polymorphism of sparteine in 49 patients with parkinsonism. Although no poor metabolizer was found in patients with Parkinsonism, mean metabolic ratio of the patients was significantly (P less than 0.05) greater than that of healthy subjects. Furthermore, the value showed a significantly negative correlation (r = -0.327, p less than 0.05) with the onset of age. In addition, the percentage of the presumed heterozygotes (metabolic ratio less than 1.4) was tended to be greater in the patients with the onset of age, younger than 49 years (10/31) than in those with the onset of age, older than 50 years (2/18). These results suggest that decreased capacity of sparteine oxidation may be one of the susceptible factors to acquire Parkinsonism in human.

Age Factors↗
PubMed1989

Subnanogram GC/NPD method for the determination of sparteine in biological fluids.

A gas chromatographic method is presented for identification and quantification of sparteine in biological fluids using cyclizine as an internal standard. No derivation is necessary and after a single alkaline extraction, GC analysis of sparteine is achieved in less than 8 min. A subnanogram limit of detection is allowed by the use of a nitrogen phosphorous detector (NPD). This method is simple, reproducible, selective, and applicable in both clinical and pharmacokinetic studies.

Chromatography, Gas↗
PubMed1989

Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design.

Nifedipine (NF), sparteine (SP), mephenytoin (MP) and antipyrine (AP) were administered simultaneously ("cocktail" design) to 15 healthy subjects, including 4 poor metabolizers (PM) of SP and 4 PMs of MP, on three different occasions: without pretreatment, after pentobarbital (PB) pretreatment and together with cimetidine (cim). Concentrations of AP, NF, its pyridine metabolite 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-methylester (M-O), SP, dehydrosparteine (DHS) were determined in plasma; 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monomethyle ster (which is ester hydrolyzed M-O), SP, DHS, 4-hydroxymephenytoin, AP and metabolites 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine were measured in urine. Clearance of NF had increased 270% after PB and decreased 32% with cim. Area under the plasma-concentration time curve of M-O and urinary excretion of 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monoethyles ter had also decreased after PB. Neither extensive metabolizers nor PMs of SP and MP were sensitive to PB treatment, but sparteine clearance was reduced 55% by cim in extensive metabolizers and 59% in PMs. Ratio SP/DHS in urine was hardly influenced by cim. AP oxidation was significantly induced and inhibited by PB and cim, respectively. The cocktail study design seems to be suitable to assess induction and inhibition of the metabolism of the applied model substrates, which are metabolized by at least partly independent isozymes of the cytochrome P-450 system, simultaneously.

Adult↗
PubMed1980

Antifibrillatory, cardiovascular and toxic effects of sparteine, butylsparteine and pentylsparteine.

The negative bathmo- ino and chronotropic effects of sparteine, butylsparteine and pentylsparteine were quantitatively determined in isolated rat atria. The antifibrillatory potency was studied in rats (aconitine arrhythmia), guinea pigs (digoxin arrhythmia) and in cats (spontaneous arrhythmia). In order to appraise the cardiovascular compatibility of these drugs, additional circulatory effects were studied in rats and cats. Acute toxicity following intravenous, intraperitoneal and oral administration was assessed in male and female mice. Pentylsparteine was more potent than sparteine and had a better therapeutic index.

Animals↗
PubMedDate not supplied

Genetically determined sparteine oxidation and sulfadimidine acetylation polymorphism in patients with non-occupational urinary bladder cancer.

The results of our study revealed a predominance of the percentage of extensive metabolizers (EM) of sparteine (94.8%) among 58 patients with non-occupational urinary bladder cancer in comparison with the percentage of extensive metabolizers (91.2%) in healthy persons; the difference being not statistically significant. However, among ultrarapid (EM) oxidators with the metabolic ratio (MR) < 0.5 the difference in the MR frequency distribution between 15 patients with bladder cancer (25.9%) and 18 healthy persons (11.25%) was statistically significant. Therefore, our studies provide some evidence of a possible relationship between the EM sparteine oxidation phenotype and the susceptibility to non-occupational bladder cancer. Not statistically significant slight prevalence of the percentage of slow acetylators (SA) (53.1%) among 32 urinary bladder cancer patients in comparison with the percentage of SA (49%) among 45 healthy persons may confirm the conclusion that a slow acetylator phenotype is not associated with the increased risk of the development of non-occupational urinary bladder cancer.

Acetylation↗
PubMed1984

Characterization of a common genetic defect of cytochrome P-450 function (debrisoquine-sparteine type polymorphism)--increased Michaelis is Constant (Km) and loss of stereoselectivity of bufuralol 1'-hydroxylation in poor metabolizers.

In order to define the mechanism of the debrisoquine-sparteine type genetic polymorphism of drug oxidation we studied the kinetics of bufuralol 1'-hydroxylation in liver microsomes from extensive and poor metabolizers and in a purified reconstituted human cytochrome P-450 isozyme with high activity for bufuralol 1'-hydroxylation, P-450[buf]. In extensive metabolizer microsomes the enzymatic reaction displayed apparent Michaelis-Menten kinetics and the (+)-isomer was preferentially metabolized. By contrast, the enzymatic reaction in poor metabolizer microsomes was characterized by a 4- to 5-fold increase in Km and by a loss of stereoselectivity. In a non-membraneous reconstituted system containing NADPH cytochrome P-450 reductase, a NADPH regenerating system and phospholipids, P-450[buf] exhibited an almost complete substrate stereoselectivity for (+)-isomer 1'-hydroxylation. It is concluded that the purified cytochrome P-450[buf] is the target of the debrisoquine-sparteine type oxidation polymorphism and that poor metabolizers have a quantitative or qualitative deficiency of this isozyme.

Cytochrome P-450 Enzyme System↗