Clozapine is effective in treatment-resistant schizophrenia; however, adverse effects often result in discontinuation of clozapine therapy. Many of the side-effects are associated with pharmacokinetic variations; therefore, the expression of major clozapine-metabolizing enzymes (CYP1A2, CYP3A4) in patients may predict development of adverse effects. In patients with schizophrenia (N = 96), development of clozapine concentration-dependent metabolic side-effects was found to be associated with pharmacokinetic variability related to CYP3A4 but not to CYP1A2 expression. In low CYP3A4 expressers, significant correlation was detected between fasting glucose level and clozapine concentration; moreover, the incidence of abnormal glucose level was associated with exaggerated clozapine concentrations (> 600 ng/ml). In low CYP3A4 expressers, exaggerated concentrations were more frequently observed than in normal/high expressers. Moderate/high risk obesity (BMI ≥ 35) more frequently occurred in low CYP3A4 expresser patients than in normal/high expressers. In patients with normal/high CYP3A4 expression and consequently with extensive clozapine-metabolizing capacity, norclozapine/clozapine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI. Low CYP3A4 expression often resulting in exaggerated clozapine concentrations was considered to be as an important risk factor for some concentration-dependent adverse effects as normal/high CYP3A4 expression evoking high norclozapine/clozapine ratios. CYP3A4-status can identify patients with increased risk for metabolic side-effects and prevent their development by careful therapeutic strategy.

Human CYP2B6 enzyme although constitutes relatively low proportion (1–4%) of hepatic cytochrome P450 content, it is the major catalyst of metabolism of several clinically important drugs (efavirenz, cyclophosphamide, bupropion, methadone). High interindividual variability in CYP2B6 function, contributing to impaired drug-response and/or adverse reactions, is partly elucidated by genetic polymorphisms, whereas non-genetic factors can significantly modify the CYP2B6 phenotype. The influence of genetic and phenoconverting non-genetic factors on CYP2B6-selective activity and CYP2B6 expression was investigated in liver tissues from Caucasian subjects (N = 119). Strong association was observed between hepatic S-mephenytoin N-demethylase activity and CYP2B6 mRNA expression (P < 0.0001). In less than one third of the tissue donors, the CYP2B6 phenotype characterized by S-mephenytoin N-demethylase activity and/or CYP2B6 expression was concordant with CYP2B6 genotype, whereas in more than 35% of the subjects, an altered CYP2B6 phenotype was attributed to phenoconverting non-genetic factors (to CYP2B6-specific inhibitors and inducers, non-specific amoxicillin + clavulanic acid treatment and chronic alcohol consumption, but not to the gender). Furthermore, CYP2B6 genotype–phenotype mismatch still existed in one third of tissue donors. In conclusion, identifying potential sources of CYP2B6 variability and considering both genetic variations and non-genetic factors is a pressing requirement for appropriate elucidation of CYP2B6 genotype–phenotype mismatch.

Adult circumcision is a delicate genital surgical procedure rather than a simple "any-one-can-do-it" intervention. Hypertrophic scar tissue formation, scar wrinkling and incomplete circumcision are the most frequent complications of an improper technique. Adequate foreskin removal, delicate atraumatic surgical technique and special suturing techniques are necessary to achieve optimal cosmetic and functional result.

High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients’ CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A5*3/*3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A5*1. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A5*1 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.

CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of CYP1A2 genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of CYP1A2 genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin O-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. CYP1A2*1F, considered to be associated with high CYP1A2 inducibility, is generally identified by the presence of −163C>A polymorphism; however, we demonstrated that −163C>A existed in several haplotypes (CYP1A2*1F, CYP1A2*1L, CYP1A2*1M, CYP1A2*1V, CYP1A2*1W), and consequently, CYP1A2*1F was a much rarer allelic variant (0.4%) than reported in Caucasian populations. Of note, −163C>A polymorphism was found to result in an increase of neither mRNA nor the activity of CYP1A2. Moreover, hepatic CYP1A2 activity was associated with hepatic or leukocyte mRNA expression rather than genetic polymorphisms of CYP1A2. Consideration of non-genetic phenoconverting factors (co-medication with CYP1A2-specific inhibitors/inducers, tobacco smoking and non-specific factors, including amoxicillin+clavulanic acid therapy or chronic alcohol consumption) did not much improve genotype–phenotype estimation. In conclusion, CYP1A2-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity.

Donor's CYP3A-status (CYP3A5 genotype and CYP3A4 expression) can provide prognostic information regarding tacrolimus-metabolizing capacity of the liver graft and initial tacrolimus dosing for therapeutic blood concentrations in liver transplants. The present work prospectively investigated whether CYP3A-status guided tacrolimus therapy has any potential clinical benefit for recipients in the early postoperative period. Methods: The contribution of preliminary assaying of donor CYP3A-status to the optimization of initial tacrolimus therapy and to the reduction of adverse events (acute rejection, infection, nephrotoxicity) was investigated in 112 liver transplant recipients (CYPtest group) comparing to 101 control patients on tacrolimus concentration guided therapy. Results: The time for achieving therapeutic tacrolimus concentration was significantly reduced, confirming potential benefit of initial tacrolimus therapy adjusted to donor's CYP3A-status over classical clinical practice of tacrolimus concentration guided treatment (4 vs 8 days, P < 0.0001). Acute rejection episodes (3.6 vs 23.8%, P < 0.0001) and tacrolimus induced nephrotoxicity (8 vs 27%, P = 0.0004) were less frequent in CYPtest group than in control patients, whereas occurrence of infectious disease was not influenced by tacrolimus dosing strategy (3.6 vs 5.9% in CYPtest and control groups, P > 0.05). Acute rejection was often accompanied with tacrolimus blood concentrations lower than 10 ng mL −1 (20/24 of control and 2/4 of CYPtest patients), while nephrotoxicity was associated with high tacrolimus concentrations (>20 ng mL −1) in the first week after transplantation (13/27 of control and 2/9 of CYPtest patients). Conclusion: CYP3A-status guided therapy significantly improved the risk of misdosing induced early adverse effects (acute rejection, nephrotoxicity).

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Despite significant changes in pediatric oncological therapy, mortality is still high, mainly due to infections. Complement system as an ancient immune defense against microorganisms plays a significant role in surmounting infections, therefore, deficiency of its components may have particular importance in malignancies. The present paper assesses the effect of promoter (X/Y) and exon 1 (A/0) polymorphisms of the MBL2 gene altering mannose binding lectin (MBL) serum level in pediatric oncological patients with febrile neutropenia. Furthermore, frequency distribution of MBL2 alleles in children with malignancies and age-matched controls was analysed. Fifty-four oncohematological patients and 53 children who had undergone pediatric surgery were enrolled into this retrospective study. No significant differences were found in the frequency of MBL2 alleles between the hemato-oncologic and control group. The average duration of fever episodes was significantly shorter (p = 0.035) in patients carrying genotypes (AY/AY and AY/AX) that encode normal MBL level, compared to individuals with genotypes associated with lower functional MBL level (AX/AX, AY/0, AX/0, or 0/0) (days, median (IQ range) 3.7(0-5.4) vs. 5.0(3.8-6.6), respectively). In conclusion, our data suggest that MBL2 genotypes may influence the course of febrile neutropenia in pediatric patients with malignancies, and may contribute to clarification of the importance of MBL in infections.