PubMed Health⌕ Search

Biomedical subjects

C Alm

Publications and source records attributed to C Alm.

29 records · Page 2Linked to original sources
PubMed1994

Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test.

In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (rs = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. N1- and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.

Administration, Oral↗
PubMed1993

Polymorphic 2-hydroxylation of desipramine. A population and family study.

We have studied desipramine hydroxylation capacity, determined as the metabolic ratio of desipramine to 2-hydroxydesipramine in the urine after a single oral dose of 10 mg of desipramine, in 340 Swedish Caucasians, including the members of 45 two-generation families. Desipramine metabolic ratios were bimodally distributed among 237 unrelated subjects and 8% were poor metabolizers. There was a strong correlation between the metabolic ratios for desipramine and debrisoquine in 337 subjects phenotyped with both drugs and there was no dissociation between their capacities to hydroxylate desipramine and debrisoquine. Complex segregation analysis in the 45 families gave evidence for a major locus with incomplete recessivity (d = 0.14) controlling the 2-hydroxylation of desipramine. Similar results were obtained in segregation analysis for debrisoquine. There was evidence for linkage between the CYP2D6 gene and the gene regulating the hydroxylation of desipramine and debrisoquine. This study has provided unequivocal evidence that the capacity to 2-hydroxylate desipramine is polymorphic and under similar genetic control to the hydroxylation of debrisoquine.

Adolescent↗
PubMed1992

Cytochrome P-450-dependent hydroxylation in migraine.

The hypothesis was tested that an acute oxidation deficiency related to potential dietary trigger factors plays a role in the migraine attack. Migraine sufferers (14F and 4M), fulfilling the criteria for migraine with and without aura according to the classification of the International Headache Society, were coadministered oral mephenytoin (100 mg) and debrisoquine (10 mg) during the initial phase of a typical migraine attack. This was repeated during a period without migraine. The hydroxylation of mephenytoin and debrisoquine hydroxylation did not differ during and without the migraine attack. We conclude that hydroxylation, via cytochrome P-450 (2D6, 2C8 and 9), is not reduced during the migraine attack. The results do not support the hypothesis that oxidation deficiency is involved in the pathophysiology of migraine.

Chromatography, Gas↗
PubMed1992

Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype.

To investigate the importance of genetic factors for the regulation of haloperidol metabolism, we studied the disposition of a single oral dose of this drug in a panel of six extensive (EM) and six poor (PM) metabolizers of debrisoquine. PM eliminated haloperidol significantly slower than EM, the plasma half-life being longer (mean 29.4 +/- S.D. 4.2 and 16.3 +/- 6.4 h; p less than 0.01) and the clearance lower (1.16 +/- 0.36 and 2.49 +/- 1.31 L/h/kg; p less than 0.05). A 4-mg dose of haloperidol was given to the first three PM, but all three developed side effects, and a 2-mg dose had to be given to the next three PM subjects. All EM received 4 mg haloperidol. The disposition of haloperidol is thus associated with the genetically determined capacity to hydroxylate debrisoquine. PM of debrisoquine (7% of Caucasian populations) might, therefore, on common doses of haloperidol, achieve high plasma concentrations and thereby have an increased risk of side effects. At the other extreme, very rapid metabolizers may need increased doses of haloperidol.

Adult↗
PubMed1990

Lack of relationship between glibenclamide metabolism and debrisoquine or mephenytoin hydroxylation phenotypes.

The pharmacokinetics of a single oral dose of 1.75 mg glibenclamide were studied in 15 healthy Caucasians including five poor metabolisers of debrisoquine and five poor metabolisers of S-mephenytoin. Plasma glibenclamide concentrations and the urinary concentrations of trans-4- and cis-3-hydroxyglibenclamide were analyzed by h.p.l.c. Thirty-six +/- 6% (mean +/- s.d., n = 15) of the given dose of glibenclamide was excreted in 48 h urine as hydroxylated metabolites, 27 +/- 4% as trans-4-hydroxyglibenclamide and 8 +/- 2% as cis-3-hydroxyglibenclamide. There were no differences in the plasma pharmacokinetics of glibenclamide or in the urinary excretion of the metabolites between poor and extensive metabolisers of debrisoquine, neither between the two mephenytoin hydroxylator phenotypes. The study thus indicates that the disposition of glibenclamide is not influenced by these two independent polymorphisms of drug oxidation.

Adult↗
PubMed1989

Disposition of perphenazine is related to polymorphic debrisoquin hydroxylation in human beings.

The pharmacokinetics of a single oral dose of 6 mg perphenazine was studied in a group of six slow and six rapid hydroxylators of debrisoquin. Peak serum concentrations of perphenazine were significantly higher in slow hydroxylators than they were in rapid hydroxylators (2.4 +/- 0.6 versus 0.7 +/- 0.3 nmol/L, p less than 0.001). The AUC(0-12) was also higher in slow hydroxylators than it was in rapid hydroxylators (18.5 +/- 6.2 versus 4.5 +/- 2.5 nmol.L-1.hr, p less than 0.001). The data suggest that the disposition of the antipsychotic drug perphenazine covaries with polymorphic debrisoquin hydroxylation.

Administration, Oral↗
PubMed1989

S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin.

Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers of mephenytoin and between debrisoquin and 4-OH-debrisoquin in urine were determined by use of GC. These ratios were used as measures of drug hydroxylation. There was no change in the phenotypic trait values of the two drugs when they were coadministered. Mephenytoin and debrisoquin then were coadministered to 253 healthy Swedish subjects, before bedtime, and urine samples were collected at periods of 0 to 8, 8 to 24, and 24 to 32 hours after drug administration. In the first sample, seven of the 253 subjects (2.8%, 95% confidence interval 0.8% to 4.8%) had an S/R ratio of greater than 0.8; this indicated that they were poor hydroxylators of S-mephenytoin. In the two consecutive samples, the S/R ratios of mephenytoin did not change in these seven persons, whereas it decreased to less than 0.2 in the third sample in the extensive hydroxylators. As was reported before, there was no relationship between the mephenytoin S/R ratio and the debrisoquin metabolic ratio (rs = 0.01). Coadministration of debrisoquin and mephenytoin before bedtime and urine collection during two consecutive nights allow for an accurate determination of both phenotypes in the population.

Adolescent↗
PubMed1989

Interindividual and interethnic differences in the demethylation and glucuronidation of codeine.

1. The 8 h urinary excretion of codeine and seven of its metabolites was compared in 149 healthy Swedish Caucasians and 133 healthy Chinese following a single oral dose of 25 mg codeine phosphate. 2. The total 8 h urinary recovery of drug-related material was 74 +/- 24% in the Caucasians and 60 +/- 14% in the Chinese (P less than 0.001). The excretion of unchanged codeine was significantly higher in the Chinese (7.2%) compared with the Caucasians (4.3%, P less than 0.001). 3. The Caucasians excreted significantly greater proportions of codeine-6-glucuronide (C6G) (62%) than the Chinese (44%) (P less than 0.001). The frequency distribution of the log metabolic ratio (MR) for glucuronidation (codeine/C6G) was shifted towards higher values in the Chinese population. Males in both groups and Chinese smokers had significantly lower glucuronidation MRs than females and non-smokers in the respective populations (P less than 0.001). 4. The frequency distribution of the MR for O-demethylation (codeine/morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM) was highly skewed in the Caucasians, suggestive of a bimodal distribution. There was a 160-fold interindividual variation in this MR. A unimodal distribution of the log O-demethylation MR was observed in Chinese. The Caucasians excreted less M and more M6G than did the Chinese (P less than 0.001). 5. Significantly more norcodeine (NC) and less NC-glucuronide (NCG) were excreted in the Chinese compared with the Caucasians (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation.

1. A single oral dose of codeine (25 mg) was given to 132 healthy Swedish Caucasians who had previously been phenotyped with respect to debrisoquine hydroxylation. The 'metabolic ratios' (MR) in urine of codeine O-demethylation (codeine/(morphine (M) + morphine-3- and 6-glucuronides (M3G and M6G) + normorphine], N-demethylation (codeine/(norcodeine (NC) + norcodeine glucuronide + normorphine (NM]) and glucuronidation (codeine/codeine-6-glucuronide (C6G] were calculated following h.p.l.c. analysis of urine samples collected over 8 h. 2. There was a significant correlation between the log MR for debrisoquine hydroxylation and the log MR for codeine O-demethylation (rs = 0.77, P less than 0.001). The poor debrisoquine hydroxylators had MRs of codeine O-demethylation between 8.3 and 55.1, while the values for extensive hydroxylators were between 0.4 and 5.5. 3. The poor debrisoquine hydroxylators excreted significantly less M, M3G, M6G and NM, while the urinary recovery of C6G and NC was significantly higher in these subjects compared to the extensive hydroxylators. 4. The MRs for glucuronidation and N-demethylation did not exhibit a bimodal distribution, and were not related to the MR of debrisoquine hydroxylation. 5. No associations were found between sex, body-weight, smoking habits, age, urine volume or urine pH and the O-demethylation of codeine. 6. The O-demethylation of codeine to form M appears to be under the same polymorphic genetic control as the 4-hydroxylation of debrisoquine.

Adolescent↗