Ilse P. van der Heiden

Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus

The calcineurin inhibitors cyclosporine (INN, ciclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P‐glycoprotein, encoded by MDR‐1.

A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients

BACKGROUND Tacrolimus (Tac) is a potent immunosuppressant with considerable toxicity. Tac pharmacokinetics varies between individuals and thus complicates its use in preventing rejection after kidney transplantation. This variability might be caused by genetic polymorphisms in metabolizing enzymes. METHODS We used TaqMan analyses to evaluate the impact of a newly discovered CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) single-nucleotide polymorphism (SNP) (rs35599367C>T; CYP3A4*22) on Tac pharmacokinetics in 185 renal transplant recipients who participated in an international randomized controlled clinical trial (fixed-dose, concentration-controlled study). RESULTS The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 33% lower for carriers of the T variant allele than for rs35599367CC patients (95% CI, -46% to -20%; P = 0.018). When combined with the *3 genotype of the CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) gene, the rs35599367C>T SNP was also associated with a risk of supratherapeutic Tac concentrations (>15 μg/L) during the first 3 days after surgery, with an odds ratio of 8.7 for carriers of the CYP3A4 T allele plus CYP3A5*3/*3 (P = 0.027) and 4.2 for the CYP3A4 CC homozygotes plus CYP3A5*3/*3 (P = 0.002), compared with CYP3A4 CC homozygotes having 1 or 2 CYP3A5*1 alleles. The overall increase in the Tac dose-adjusted trough blood concentration was +179% for carriers of the CYP3A4 T allele with CYP3A5*3/*3 (P < 0.001), +101% for CYP3A4 CC homozygotes with CYP3A5*3/*3 (P < 0.001), and +64% for CYP3A4 T allele carriers with CYP3A5*1 (P = 0.020),compared with CYP3A4 CC homozygotes with CYP3A5*1. CONCLUSIONS The CYP3A4 rs35599367C>T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation. Analysis of this CYP3A4*22 SNP may help in identifying patients at risk of Tac overexposure.

Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes

Our objective was to determine the relationship between single nucleotide polymorphisms (SNPs) in the multidrug resistance 1 (MDR‐1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 and the pharmacokinetics of cyclosporine (INN, ciclosporin).

Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration

Background and objective Digoxin is a known substrate of ATP-binding cassette B1 (ABCB1/MDR1). The results of studies on the association between ABCB1 polymorphisms and digoxin kinetics, however, remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population. Methods Digoxin users were identified in the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years and above. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 single nucleotide polymorphisms (SNPs) 1236C→T, 2677G→T/A, and 3435C→T were assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes, and digoxin blood levels using linear regression models adjusting for potential confounders. Results Digoxin serum levels and DNA were available for 195 participants (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18–0.21 μg/l per additional T allele). The association was even stronger for the 1236–2677–3435 TTT haplotype allele [0.26 μg/l (95% CI 0.14–0.38)], but absent for other haplotypes (CGC allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects. Conclusion We found that the common ABCB1 1236C→T, 2677G→T, and 3435C→T variants and the associated TTT haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population.

Propofol Pharmacokinetics and Pharmacodynamics for Depth of Sedation in Nonventilated Infants after Major Craniofacial Surgery

Background: To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described. Methods: After craniofacial surgery, 22 of the 44 evaluated infants (aged 3–17 months) in the pediatric intensive care unit received propofol (2–4 mg · kg−1 · h−1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). Results: In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 · (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index. Conclusions: Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12–14 on the COMFORT-Behavior scale and 70–75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.

ABCB1 gene polymorphisms are not associated with treatment outcome in elderly acute myeloid leukemia patients.

The classical multidrug resistance (MDR) gene MDR1 (ABCB1) encodes for the drug efflux pump P‐glycoprotein (P‐gp). P‐gp expression is an adverse prognostic factor for treatment outcome in acute myeloid leukemia (AML) and is more frequently observed in older patients. Single‐nucleotide polymorphisms of the ABCB1 gene, C1236T, G2677T, and C3435T, have been associated with altered drug metabolism and treatment outcome. We prospectively determined these single‐nucleotide polymorphisms in AML blasts in a cohort of patients aged 60 years or older with AML and evaluated their relevance with regard to P‐gp function and expression, ABCB1 messenger ribonucleic acid (mRNA) expression, and clinical outcome.

Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia

PurposeThe basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo.MethodsPlasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR).ResultsPlasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89–128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients’ sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p = 0.02) as shown by the weight-corrected area under the time–plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup.ConclusionsNo significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.

Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with cleft lip with or without cleft palate†

Gene–environment interactions in the periconceptional period play an increasing role in the pathogenesis of birth defects, including cleft lip and/or cleft palate (CL/P). The P‐glycoprotein, encoded by the ABCB1 gene, is suggested to protect the developing embryo from medication and other xenobiotic exposures. Furthermore, maternal medication use during early pregnancy is a significant risk factor for CL/P offspring. Therefore, the aim of this study is to investigate the association between the maternal and childs functional ABCB1 3435C > T polymorphism, periconceptional medication exposure, and the risk of a child with CL/P. A case–control study was performed among 175 mothers and 98 of their children with CL/P and 83 control mothers and their 65 children. Information on medication and folic acid use was collected. Mothers carrying the 3435TT genotype and using medication showed a 6.2‐fold (95% CI = 1.6–24.2) increased risk of having a child with CL/P compared to mothers carrying the 3435CC genotype and not using medication. Periconceptional folic acid use reduced this risk by approximately 30% (OR = 3.9, 95% CI = 0.9–18.0). Mothers carrying the 3435TT genotype, using medication and not taking folic acid showed the highest risk estimate (OR = 19.2, 95% CI = 1.0–369.2). These data suggest that mothers who carry the ABCB1 3435C > T polymorphism are at significantly increased risk for having offspring with CL/P, especially mothers using medication in the periconceptional period.

General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect

OBJECTIVE We sought to investigate maternal and child functional MDR1 C3435T polymorphism, periconception medication, folic acid use, and the risk of a congenital heart defect (CHD) in the offspring. STUDY DESIGN MDR1 3435C>T genotyping was performed in 283 case triads (mother, father, child) and 308 control triads. Information on periconception medication and folic acid use was obtained through questionnaires. RESULTS Mothers with MDR1 3435CT/TT genotype and using medication showed a significant association with the risk of a child with CHD (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3-4.3) compared to mothers with MDR1 3435CC genotype not using medication. This risk increased without folic acid use (OR, 2.8; 95% CI, 1.2-6.4), and decreased in folic acid users (OR, 1.7; 95% CI, 0.8-3.7). Children carrying the MDR1 3435CT/TT genotype and periconceptionally exposed to medication without folic acid did not show significant risks. CONCLUSION Mothers carrying the MDR1 3435T allele, using medication without folic acid, are at nearly 3-fold increased risk for CHD in the offspring.

Mycophenolic acid-related diarrhea is not associated with polymorphisms in SLCO1B nor with ABCB1 in renal transplant recipients.

ObjectiveWe investigated the association between genetic polymorphisms in ABCB1 and SLCO1B and mycophenolic acid (MPA) pharmacokinetics, and MPA-related diarrhea and leukopenia in 338 kidney transplant recipients. MethodsA total of 338 patients participating in an international, randomized-controlled clinical trial were genotyped for ABCB1 and SLCO1B. Patients were all treated with mycophenolate mofetil and either cyclosporine or tacrolimus. MPA-area under the curve (AUCs), MPA-glucuronide AUCs and acylglucuronide-AUCs were measured on days 3 and 10, and months 1, 3, 6, and 12 after kidney transplantation. ResultsThe risk of developing diarrhea was 1.8-fold higher in patients cotreated with tacrolimus compared with patients cotreated with cyclosporine (95% confidence interval: 1.03–3.13; P=0.038). ABCB1 and SLCO1B SNPs were not associated with dose-adjusted exposure to MPA, MPA-glucuronide, nor acylglucuronide-MPA nor with the incidence of diarrhea or leukopenia. ConclusionGenotyping for ABCB1 or SLCO1B pretransplantation is unlikely to be of clinical value for individualization of MPA therapy.