Aims To investigate pharmacokinetics of the enantiomers of citalopram (CT) and its metabolites desmethylcitalopram (DCT) and didesmethylcitalopram (DDCT) in Swedish healthy volunteers in relation to CYP2C19 and CYP2D6 geno-and phenotypes. Methods Racemic CT was given for seven days to panels with different genotypes and the following mephenytoin (Me) and debrisoquine (De) hydroxylation phenotypes: EM De /EM Me , PM De /EM Me , EM De /PM Me ( n = 6 in all groups), and one PM De / PM Me subject. Blood sampling was carried out during day 7, and all urine was collected for 12 h after the last dose of CT. Results The AUC of S-CT was significantly higher in the EM De /PM Me panel compared to the EM De /EM Me and PM De /EM Me panels ( P < 0.05), whereas the AUC of R-CT did not differ between the panels. Similar differences, although they did not reach statistical significance, were noted for S-DCT and R-DCT. The enantiomers of DDCT were not quantifiable in PM De, and there was no difference in DDCT enantiomer concentrations between the other two panels. A PM De /PM Me subject stopped taking CT after five days due to severe adverse effects. Based on two time points, this subject had a very long CT half-life of 95 h. The value of 1.0 for the S/R ratio of the CT trough in this subject was similar to the mean S/R CT trough ratio of the EM De /PM Me panel, but higher than the S/R CT ratio of the EM De /EM Me panel (0.56; 95% CI 0.49-0.63) and the PM De /EM Me panel (0.44; 95% CI 0.31-0.57). Thus the latter two phenotypes eliminated S-CT more rapidly via CYP2C19. An adverse effect described as an 'alcohol hangover' feeling was reported by one subject from each of the three panels. These individuals had the highest concentrations of both CT enantiomers. Conclusions The AUC of S-, but not R-(CT) was found to be significantly higher in PM of mephenytoin compared to EMs, PMs may need a lower dosage of CT.
Black Africans show lower rates of CYP2D6- and CYP2C19-dependent drug metabolism compared to Caucasians of the same apparent genotype. To determine if environmental factors are responsible for this difference, the genotypes and phenotypes of CYP2D6 and CYP2C19 among Ethiopians living in Sweden (n = 70) were assessed and compared to our previously published data from Ethiopians living in Ethiopia (n = 114) and Swedish Caucasians (n = 134). There was no significant difference in CYP2C19 genotype or phenotype as assessed by mephenytoin between Ethiopians in Sweden or in Ethiopia. However, Swedes were significantly more rapid for CYP2C19 activity than both Ethiopian groups (P < 0.01). A comparison of the debrisoquine MR among individuals of the same CYP2D6 genotype revealed that Swedes exhibited the highest rate of debrisoquine metabolism, followed by Ethiopians in Sweden and Ethiopians in Ethiopia. The difference between the Ethiopian groups was significant (P < 0.02 using a univariate test ANOVA) and amounted to approximately 50% of the magnitude of the MR difference between Swedes and Ethiopians in Ethiopia. It is tempting to speculate that inhibitory dietary factors may explain the differences seen between the two Ethiopian groups and that these components in the past might have contributed to dietary stress-mediated selection of duplicated and multiduplicated active CYP2D6 genes, as frequently seen in Ethiopians. In conclusion, the results indicate a significant influence of environmental factors as an explanation for the difference in capacity for CYP2D6, but not CYP2C19 metabolism between Caucasians and Black Africans. Additional factors remain to be elucidated to fully explain the interethnic differences in CYP2D6 activity.
Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population.
Summary
The occurrence of progressive cerebral symptoms is described in a juvenile form of Gaucher's disease, in a clinical series assessed uniformly. This series is composed of six persons, still living, between the ages of 6 and 20, belonging to four related families, who all come from a limited area in northern Sweden. All 6 patients have shown the same clinical, his to pathological and his to chemical findings, and all have undergone splenectomy. Two spleens were chemically analysed. Their lipid content was typical of Gaucher's disease. All cases developed skeletal changes within 31/2 years of splenectomy.
The cerebral signs consisted of mental retardation in 5 cases, psychotic behaviour disorders in 2 cases, generalised rigidity and jerky movement in 5, epilepsy in 3 and a pathological EEG in them all. Similar signs were not found among the children's relatives.
The progressive mental and neurological symptoms indicate a diffuse, progressive encephalopathy, which affects the cortical and sub cortical grey matter. The authors think it likely that the cerebral signs have a vascular origin and are caused by deposition of cerebrosides in the adventitital cells of the cerebral blood vessels. Similar cerebral changes have been described in the infantile form of Gaucher's disease. Splenectomy performed at an early age may have been a provocative factor in the development of these hypothetical vascular changes and of the early skeletal changes.
As shown in an earlier study, also with a third substrate, Tanzanians have a lower capacity to form cycloguanil than white and Asian subjects. Individuals with two mutated alleles have lower metabolic capacity than individuals with two wild-type alleles or individuals in the heterozygous group, which may lead to chloroguanide therapeutic failure. This knowledge should be important when selecting appropriate patients and doses of chloroguanide in different populations.
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