Guillermo Gervasini

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 (r 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.

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.

Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation

We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.

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

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.

Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy

Genetic factors contribute to the phenotype of drug response, but the translation of pharmacogenetic outcomes into drug discovery, drug development or clinical practice has proved to be surprisingly disappointing. Despite significant progress in pharmacogenetic research, only a few drugs, such as cetuximab, dasatinib, maraviroc and trastuzumab, require a pharmacogenetic test before being prescribed. There are several gaps that limit the application of pharmacogenetics based upon the complex nature of the drug response itself. First, pharmacogenetic tests could be more clinically applicable if they included a comprehensive survey of variation in the human genome and took into account the multigenic nature of many phenotypes of drug disposition and response. Unfortunately, much of the existing research in this area has been hampered by limitations in study designs and the nonoptimal selection of gene variants. Secondly, although responses to drugs can be influenced by the environment, only fragmentary information is currently available on how the interplay between genetics and environment affects drug response. Third, the use of a pharmacogenetic test as a standard of care for drug therapy has to overcome significant scientific, economic, commercial, political and educational barriers, among others, in order for clinically useful information to be effectively communicated to practitioners and patients. Meanwhile, the lack of efficacy is in this process is quite as costly as drug toxicity, especially for very expensive drugs, and there is a widespread need for clinically and commercially robust pharmacogenetic testing to be applied. In this complex scenario, therapeutic drug monitoring of parent drugs and/or metabolites, alone or combined with available pharmacogenetic tests, may be an alternative or complementary approach when attempts are made to individualize dosing regimen, maximize drug efficacy and enhance drug safety with certain drugs and populations (e.g. antidepressants in older people).

CYP1A1 gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study

BackgroundA rural region in south-west Spain has one of the highest lung cancer incidence rates of the country, as revealed by a previous epidemiological 10-year follow-up study. The present work was undertaken to ascertain the role of CYP1A1 gene polymorphisms and their interaction with tobacco smoking in the development of the disease in this location.MethodsOne-hundred-and-three cases of lung cancer and 265 controls participated in the study. The participants were screened for the presence of four CYP1A1 polymorphisms, namely MspI, Ile462Val, T3205C, and Thr461Asn. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression models adjusting for age, sex, and smoking.ResultsThe distribution of the variant CYP1A1 alleles was different from that described for other Caucasian populations, with CYP1A1*2A showing an uncommonly high frequency (p < 0.01). The CYP1A1*2B allele (carrying MspI and Ile462Val mutations) was strongly associated with high lung cancer risk (OR = 4.59, CI:1.4-12.6, p <0.01). The Ile462Val polymorphism was also shown to increase the risk for the disease (OR = 4.51, CI:1.8-11.9; p <0.01) and particularly for squamous-cell (OR = 5.01; CI: 1.6-14.3, p < 0.01) and small-cell lung carcinoma (SCLC) (OR = 6.97, CI: 1.2-81.3; p = 0.04). Moreover, the Thr461Asn polymorphism was found to be associated with SCLC in a Caucasian population for the first time to our knowledge (OR = 8.33, CI: 1.3-15.2, p = 0.04).ConclusionThe results suggest that CYP1A1 polymorphisms contribute to increase lung cancer susceptibility in an area with an uncommon high incidence rate.

Central nervous system chemotoxicity during treatment of pediatric acute lymphoblastic leukemia/lymphoma

In the last decades, increasing success rates are being obtained in the chemotherapy of pediatric leukemia and lymphoma. However, the cornerstone of this treatment is still formed by a reduced number of drugs with a highly toxic profile. In particular, central nervous system complications remain a challenging clinical problem, requiring rapid detection and prompt treatment to limit permanent damage. Furthermore, clinicians are often challenged to discriminate between CNS involvement by the disease, toxicity of drugs or infections. This clinically oriented review will help recognize and handle the main neurologic adverse effects induced by chemotherapy in pediatric patients with lymphoblastic leukemia/lymphoma. Different clinical entities and putative drugs involved are discussed in each chapter, with clinical cases illustrating the most relevant and challenging events. In addition, specific clinical-radiological patterns of some of these neurologic events are detailed. Finally, the role of pharmacogenetics, with special focus on those polymorphisms that could help explain the occurrence of neurotoxicity, is also discussed.

Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia

The efficacy of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) patients has significantly increased in the last 20 years; as a result, the focus of research is slowly shifting from trying to increase survival rates to reduce chemotherapy-related toxicity. At the present time, the cornerstone of therapy for ALL is still formed by a reduced number of drugs with a highly toxic profile. In recent years, a number of genetic polymorphisms have been identified that can play a significant role in modifying the pharmacokinetics and pharmacodynamics of these drugs. The best example is that of the TPMT gene, whose genotyping is being incorporated to clinical practice in order to individualize doses of mercaptopurine. However, there are additional genes that are relevant for the metabolism, activity, and/or transport of other chemotherapy drugs that are widely use in ALL, such as methotrexate, cyclophosphamide, vincristine, L-asparaginase, etoposide, cytarabine, or cytotoxic antibiotics. These genes can also be affected by genetic alterations that could therefore have clinical consequences. In this review we will discuss recent data on this field, with special focus on those polymorphisms that could be used in clinical practice to tailor chemotherapy for ALL in order to reduce the occurrence of serious adverse effects.

GST Polymorphisms Interact With Dietary Factors to Modulate Lung Cancer Risk: Study in a High-Incidence Area

The aim of this study was to explore possible correlations between glutathione S-transferases (GST) polymorphisms, smoking, diet, and lung cancer susceptibility in a rural Spanish region with one of the highest incidence rates of the country. All lung cancer patients living in the area (103) and 247 matched controls were genotyped for the GST mu 1 (GSTM1) null, GST theta 1 (GSTT1) null, and GST pi 1 (GSTP1) Isoleucine (Ile) 105 valine (Val) polymorphisms and interviewed to gather information on smoking and dietary habits. Neither the presence of GST polymorphisms nor their interaction with smoking was independently associated to lung cancer risk. The intake of carotenoid-rich red and yellow vegetables was inversely associated with lung cancer (P < 0.05). Interestingly, this was observed only in carriers of the GSTM1 (P = 0.04), GSTT1 (P = 0.03), or GSTM1/T1 (P = 0.04) positive genotypes. Similarly, the consumption of citrus fruits was more frequent among cancer-free subjects who carried functional GSTM1 (P = 0.04) or both GSTM1 and GSTT1 enzymes (P = 0.04). The results show that the inverse association observed between the intake of dietary carotenoid-rich vegetables and lung cancer risk is dependent on the GST genotype. These results warrant further investigations to confirm the observed associations.

N‐acetyltransferase‐2 (NAT2) Gene Polymorphisms and Enzyme Activity in Serbs: Unprecedented High Prevalence of Rapid Acetylators in a White Population

The aim of this study was to investigate N‐acetyltransferase 2 (NAT2) genetic polymorphism and enzyme activity in Serbs, and to examine the influence of NAT2 genotype, sex, and smoking on the phenotype. Genotyping for 190C>T, 282C>T, 341T>C, 403C>G, 411T>A, 481C>T, 590G>A, 803A>G, and 857G>A in the NAT2 gene, was performed in 140 healthy Serbs. NAT2 activity was determined as AFMU/(AFMU + 1X + 1U) urinary ratio in 100 subjects using caffeine as a probe. The most frequent NAT2 haplotypes were NAT2*5B (38.2%), NAT2*6A (26.0%), and NAT2*4 (24.4%). The log‐transformed NAT2 activity indices exhibited trimodal distribution with 9%, 36%, and 55% of slow, intermediate, and rapid acetylators, respectively. Significant NAT2 genotype‐phenotype correlation was observed (P < .0001). The frequency of NAT1*10 and NAT1*11 were 27.5% and 6.9%, respectively. There was no significant influence of sex or cigarette smoking on NAT2 enzyme activity. Eight subjects displayed rapid NAT2 acetylators phenotype despite being homozygous for NAT2 slow alleles, and NAT1 fast acetylators genotype (NAT1*10 and NAT1*11) had no implication. In contrast to other white populations described hitherto, rapid acetylator is the predominant NAT2 phenotype in Serbs. NAT2 genotype, but not sex and cigarette smoking, influence enzyme activity. NAT1 fast acetylators genotypes do not contribute for NAT2 genotype‐phenotype discordance.