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Biomedical subjects

Juan Antonio Carrillo

Publications and source records attributed to Juan Antonio Carrillo.

11 recordsLinked to original sources
PubMed2006

Adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T/A gene polymorphism is associated with high risk of lung cancer.

BACKGROUND: P-glycoprotein (P-gp) is a transmembrane transporter that is encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) gene, which plays a role in cell defense against environmental attacks, like those generated by xenobiotics. P-gp is expressed in the lung, where it has been suggested to transport these compounds from the interstitium into the lumen. METHODS: Two functional ABCB1 polymorphisms were examined, G2677T/A (in exon 21) and C3435T (in exon 26), in a group of lung cancer patients and in a control group. RESULTS: Whereas 3435T allelic and genotype frequencies were unchanged between both study groups, lung cancer patients showed higher frequency of the 2677T variant allele compared with the control group (0.67 vs. 0.43; P < .001; odds ratio, [OR], 2.6; 95% confidence interval [95% CI], 1.7-4.0). Among the histologic tumor types that were included in the study, squamous cell carcinoma was associated most strongly with the presence of the 2677T allele (OR, 3.92; 95% CI, 2.2-6.9) and especially was associated with the 2677 TT genotype (OR, 6.75; 95% CI, 3.0-15.2). In a haplotype analysis, homozygous wild-type alleles were classified as genotype A, heterozygous alleles were classified as genotype B, and homozygous mutant allele were classified as genotype C both in exon 21 (first letter) and in exon 26 (second letter) loci. The haplotype CB displayed the highest association with lung cancer (OR, 18.09; 95% CI, 2.4-139.2). CONCLUSIONS: The current results taken together suggest that, aside from other known causes of lung cancer, such as tobacco smoke, the existence of polymorphisms in the ABCB1 gene and, specifically, the presence of the G2677T mutation can be crucial in conferring susceptibility to lung cancer. Further studies comprising larger populations are needed to confirm these preliminary findings.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 polymorphisms and gender on the urinary excretion of the metabolites of the H-receptor antihistamine ebastine: a pilot study.

AIMS: To determine the effect of gender and the genetic polymorphisms of CYP2J2, CYP3A4, CYP3A5 and MDR1 on the urinary excretion of the H(1) antihistamine ebastine in healthy subjects. METHODS: Eighty-nine Caucasians were studied. The presence of polymorphisms in genes known to be involved in ebastine metabolism and transport (CYP2J2*2,*3,*4,*6,*7, CYP3A4*1B, CYP3A5*3, *6 and MDR1(ABCB1)(C3435T)) was assessed by means of PCR-restriction fragment length polymorphism and sequencing methods. Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice. RESULTS: Women excreted statistically greater amounts of desalkylebastine in urine (mean +/- SD (95% confidence intervals, 95% CI), 23.0 +/- 19.5 (18.1, 27.9) micromol) than men (12.4 +/- 11.0 (7.9, 16.9)), (mean difference: 10.6 (2.4, 18.7), P < 0.005). The CYP2J2, CYP3A4 and CYP3A5 analysed polymorphisms did not greatly affect ebastine metabolite excretion. The MDR1(C3435T) polymorphism was found to affect both the urinary excretion of the active metabolite carebastine (32.3 +/- 18.3 (23.1, 41.4), 22.8 +/- 14.7 (18.6, 27.0) and 21.5 +/- 15.3 (14.7, 28.3) for CC, CT and TT carriers, respectively; P < 0.05) and the grapefruit juice-induced inhibition of its transport/formation (mean fold-decrease +/- SD (95% CI), 1.5 +/- 0.8 (1.0, 2.0), 1.1 +/- 0.9 (0.7, 1.4) and 0.9 +/- 0.4 (0.6, 1.2) for CC, CT and TT carriers, respectively; P = 0.01). CONCLUSIONS: Gender and the presence of the MDR1(C3435T) polymorphism both influence the excretion of ebastine metabolites in urine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Differences in CYP3A5*3 genotype distribution and combinations with other polymorphisms between Spaniards and Other Caucasian populations.

The goal of this study was to detect genotypic differences between Spaniards and other related populations regarding CYP3A4*1B, CYP3A5*3, and ABCB1 (MDR1) C3435T polymorphisms. DNA from 177 Spanish patients were analyzed for the presence of these mutations using PCR-restriction fragment length polymorphism or direct sequencing. The observed frequencies for CYP3A4*1B, CYP3A5*3, and C3435T alleles were within normal values in Caucasians (0.04, 0.91, and 0.5, respectively). However, 2.8% of the patients were homozygous for the wild-type CYP3A5*1 allele, an extremely uncommon genotype in other Caucasians. In addition, analysis of CYP3A4-3A5 haplotypes revealed the existence of 2 unusual subgroups: patients who were homozygous wild-type for both polymorphisms, and patients showing a CYP3A4*1A/*1B-CYP3A5*3/*3 genotype combination. The incidence of CYP3A5*1/*1 carriers and the occurrence of subjects combining the 2 above-mentioned unusual genotype combinations were more frequent in Spanish-Caucasians compared with American- or European-Caucasians. ABCB1 C3435T genotype frequencies were equally distributed between both single and combined CYP3A4 and 3A5 genotypes. These findings suggest that dose requirements for drugs metabolized by CYP3A and certain allele-disease association studies in white populations could show discrepancies in Spaniards.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Evaluation of a drug-drug interaction alert structure through the retrospective analysis of statins-macrolides co-prescriptions.

The aim of this work was the evaluation of the existent drug interaction alert structure in Spain, which is based on yellow cards notifications and circulation of drug alert letters, through the retrospective analysis of CYP3A-metabolized statins and macrolides co-prescriptions in the Spanish province of Badajoz between May and September 2001. The period of study was planned to include the release of 2 drug alert letters released by the Spanish Drug Agency in June and July, addressed to all healthcare professionals, which warned against the concomitant prescription of statins and inhibitors of their metabolism, e.g. macrolides antibacterials. 4,600,764 prescriptions were examined, 664 of which corresponded to combinations of statins and macrolides. Although a decrease was detected in the number of these co-prescriptions throughout the study, 80 of these corresponding to 67 patients were still being prescribed in September, after the warnings by the Spanish Drug Agency had been released. 431 physicians prescribed these drugs simultaneously, with 22.9% of them having more than one patient at potential risk. Doctors working at rural healthcare centres or not directly attached to any healthcare facility were more prone to prescribe unsafe coprescriptions than those working at urban health centre. This study shows that the present drug alert system is not fully efficient when facing a situation like the one retrospectively reviewed in this study, in which a prompt action, in this case termination of potentially hazardous coprescriptions, was required. New systems developed to improve prescribing, including a new method based on personal contact between Drug Surveillance Centres and general practitioners, are discussed.

Aged↗
PubMed2004

Potential role of cerebral cytochrome P450 in clinical pharmacokinetics: modulation by endogenous compounds.

Cytochrome P450 (CYP) enzymes catalyse phase I metabolic reactions of psychotropic drugs. The main isoenzymes responsible for this biotransformation are CYP1A2, CYP2D6, CYP3A and those of the subfamily CYP2C. Although these enzymes are present in the human brain, their specific role in this tissue remains unclear. However, because CYP enzymatic activities have been reported in the human brain and because brain microsomes have been shown to metabolise the same probe substrates used to assess specific hepatic CYP activities and substrates of known hepatic CYPs, local drug metabolism is believed to be likely. There are also indications that CYP2D6 is involved in the metabolism of endogenous substrates in the brain. This, along with the fact that several neurotransmitters modulate CYP enzyme activities in human liver microsomes, indicates that CYP enzymes present in brain could be under various regulatory mechanisms and that those mechanisms could influence drug pharmacokinetics and, hence, drug response. In this paper we review the presence of CYP1A2, CYP2C9, CYP2D6 and CYP3A in brain, as well as the possible existence of local brain metabolism, and discuss the putative implications of endogenous modulation of these isoenzymes by neurotransmitters.

Animals↗
PubMed2003

Xanthine oxidase activity is influenced by environmental factors in Ethiopians.

OBJECTIVES: To investigate xanthine oxidase (XO) polymorphism in Ethiopians and influence of environmental factors, smoking habit and gender-related differences on enzyme activity among Ethiopians living in Ethiopia or Sweden. METHODS: One hundred healthy unrelated Ethiopians living in Ethiopia and 73 living in Sweden participated in the study. Subjects received a 100-mg oral dose of caffeine before bedtime. All urine voided in the following 8 h was collected and the concentrations of 1-methyluracil (1U) and 1-methylxanthine (1X) micromol/l) were analyzed by means of high-performance liquid chromatography. The 1U/(1X+1U) metabolic ratio (MR) was calculated and used as an index of XO activity. RESULTS: XO activity was not normally distributed ( P<0.0001; Shapiro-Wilk's test). The incidence of putative XO poor metabolizers in Ethiopians was 4%. The effect of differences in country of residence, gender and smoking habit was analyzed using three-way ANOVA/MANOVA. The post-hoc test ( P<0.05) and Kruskal-Wallis ANOVA ( P<0.004), median test showed a significant difference in XO activity among Ethiopians living in Ethiopia compared with those living in Sweden, the activity being higher in Ethiopians living in Ethiopia. The 95% CI for differences between the two means was (0.012; 0.044). No significant difference was observed in XO MR between men and women or between smokers and non-smokers, the 95% CI for the differences being (-0.059; 0.037) and (-0.010; 0.016) respectively. CONCLUSION: The XO activity is polymorphic in Ethiopians. Neither gender nor smoking-related differences influenced XO activity but the difference in activity between Ethiopians living in Sweden or in Ethiopia indicates influence of other environmental factors such as dietary habits on XO activity.

Black People↗
PubMed2003

Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine.

This study investigated whether the smokinginducible cytochrome P450 (CYP) 1A2 and the polymorphic CYP2D6 play significant roles in the metabolism of olanzapine and its clinical effects at steady-state treatment. Caffeine and debrisoquine were used as measures of CYP1A2 and CYP2D6, respectively. After drug therapy for 15 days, the effect of olanzapine on the activities of CYP1A2 and CYP2D6 was also examined. Seventeen psychiatric patients (9 men and 8 women) were orally administered olanzapine, at a mean +/- standard deviation (SD) dosage of 10 mg/d for all smokers (n = 8) and 7.5 +/- 2.5 mg/d (range, 5-10 mg) for nonsmokers (n = 9;p <0.01). The plasma concentration-to-dose (C:D) ratio was closely correlated to the CYP1A2 activity ( s = -0.89;p <0.0001). The mean urinary caffeine indexes of nonsmokers and smokers were 17 +/- 8 and 101 +/- 44, respectively, indicating that smoking had induced a sixfold higher CYP1A2 activity (p <0.0001). Likewise, the olanzapine plasma C:D ratio (ng.mL.mg) was about fivefold lower in smokers (7.9 +/- 2.6) than in nonsmokers (1.56 +/- 1.1;p <0.0001). On day 15 of the antipsychotic therapy, the percentage decrease in Brief Psychiatric Rating Scale (BPRS) total score relative to the predosing score (in the drug-free period) was higher for nonsmokers than for smokers (30.4 +/- 10% vs. 12.5 +/- 14%;p <0.01). Six nonsmokers and three smokers experienced side effects with olanzapine. After 15 days of drug treatment, olanzapine had caused significant (p <0.0001) and substantial CYP1A2 inhibition (by 50%) in comparison with predosing values, and such inhibition can contribute to adverse drug interactions. In conclusion, smoking-induced increased CYP1A2 activity significantly diminished plasma olanzapine concentrations and the antipsychotic effect of the drug. The performance of a simple caffeine test may assist in individualization of the olanzapine dosage.

Adult↗
PubMed2003

Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1.

CYP1A2 polymorphism has been well studied in white persons and Asians but not in Africans. We performed CYP1A2 genotype and phenotype analysis using caffeine in Ethiopians living in Ethiopia (n = 100) or in Sweden (n = 73). We sequenced the CYP1A2 gene using genomic DNA from 12 subjects, which revealed a novel intron 1 single-nucleotide polymorphism (SNP), -730C>T. We developed SNP-specific polymerase chain reaction-restriction fragment length polymorphism genotyping and molecular haplotyping methods for the intron 1 SNPs, and four different haplotypes were identified: CYP1A2*1A (wild-type for all SNPs), CYP1A2*1F (-164A), CYP1A2*1J (-740G and -164A), and CYP1A2*1K (-730T, -740G, and -164A), having frequencies of 39.9, 49.6, 7.5, and 3.0%, respectively. The frequency of CYP1A2*1J and CYP1A2*1K among Saudi Arabians (n = 136) was 5.9% and 3.6%, and among Spaniards (n = 117) 1.3% and 0.5%, respectively. Functional significance of the different intron 1 haplotypes was analyzed. Subjects with CYP1A2*1K had significantly decreased CYP1A2 activity in vivo, and reporter constructs with this haplotype had significantly less inducibility with 2,3,7,8-tetrachlorodibenzo-p-dioxin in human B16A2 hepatoma cells. Electrophoretic mobility shift assay using nuclear extracts from B16A2 cells revealed a specific DNA binding protein complex to an Ets element. Efficient competition was obtained using oligonucleotide probes carrying the wt sequence and Ets consensus probe, whereas competition was abolished using probes with the -730C>T SNP alone or in combination with -740T>G (CYP1A2*1K). The results indicate a novel polymorphism in intron 1 of importance for Ets-dependent CYP1A2 expression in vivo and inducibility of the enzyme, which might be of critical importance for determination of interindividual differences in drug metabolism and sensitivity to carcinogens activated by CYP1A2.

Adult↗
PubMed2002

Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19).

OBJECTIVES: Fluvoxamine is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 and the smoking-inducible CYP1A2. Therapeutic doses of fluvoxamine inhibit both CYP1A2 and CYP2C19. In this study we used extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquin (INN, debrisoquine) (CYP2D6) and two probes, caffeine (CYP1A2) and omeprazole (CYP2C19), to investigate whether nontherapeutic doses of fluvoxamine inhibit CYP1A2 but possibly not CYP2C19. METHODS: Single oral doses of 100 mg caffeine and 20 mg omeprazole were given separately to 5 EMs and 5 PMs of debrisoquin to assess the activity of CYP1A2 and CYP2C19, respectively. Initially, a single oral dose of fluvoxamine (25 mg to PMs and 50 mg to EMs) was given, followed by 1 week of daily administration of 25 mg x 2 to EMs and 25 mg x 1 to PMs. Caffeine (day 6) and omeprazole (day 7) were again administered at the steady state of fluvoxamine. Later the study protocol was repeated with a lower dose of fluvoxamine, 10 mg x 2 to EMs and 10 mg x 1 to PMs for 1 week. Concentrations of fluvoxamine, caffeine, omeprazole, and their metabolites were analyzed by HPLC methods in plasma and urine. RESULTS: The kinetics of fluvoxamine were not significantly different in EMs and PMs after a single oral dose of the drug. At the higher but not the lower steady-state dose of fluvoxamine, a significantly lower clearance in PMs compared with EMs was observed (geometric mean, 0.86 versus 1.4 L/h per kilogram; P <.05). At steady state, the 25 mg x 1 or x 2 fluvoxamine dose caused a pronounced inhibition of about 75% to 80% for both CYP1A2 and CYP2C19, whereas the inhibition after the lower 10 mg x 1 or x 2 dose was about 40% to 50%. The area under the plasma concentration-versus-time curve from 0 to 24 hours [AUC(0-24)] of caffeine increased 5-fold (P <.001) after the higher dose of fluvoxamine and 2-fold (P <.05) after the lower dose. The area under the plasma concentration-time curve from time zero to 8 hours [AUC(0-8)] ratio of 5-hydroxyomeprazole/omeprazole decreased 3.4-fold (P <.001) and 2.4-fold (P <.001), respectively. One EM subject had a very low oral clearance of fluvoxamine after both single and multiple dosing of the drug. This subject might have a deficient transporter protein in the gut, leading to an increased absorption of fluvoxamine. CONCLUSION: No convincing evidence was found that CYP2D6 is an important enzyme for the disposition of fluvoxamine. Other factors seem to be more important. A nontherapeutic oral daily dose of fluvoxamine is sufficient to provide a marked inhibition of both caffeine (CYP1A2) and omeprazole (CYP2C19) metabolism. It was not possible to separate the inhibitory effects of fluvoxamine on these enzymes, even after such a low daily dose such as 10 mg x 1 or x 2 of fluvoxamine.

Adrenergic Agents↗