Pharmacogenetic information in Swiss drug labels - a systematic analysis.

Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% (n = 93) were classified as "actionable PGx". Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group "nervous system". Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.

Compartment-specific gene regulation of the CAR inducer efavirenz in vivo.

Nuclear receptors such as the constitutive androstane receptor (CAR) are central factors that link drug exposure to the activities of drug metabolism and elimination. In order to determine the in vivo effects of efavirenz, a CAR activator, the expression of target genes was determined in duodenal biopsies obtained from 12 healthy volunteers before treatment and after 10 days of treatment with efavirenz; concomitant administration of the cholesterol inhibitor ezetimibe produced no significant difference. However, in in vitro studies, efavirenz significantly increased CYP2B6 expression in several cell types, suggesting that the drug transactivates CAR. This hypothesis is supported by our findings that there is significant induction of CAR target genes in in vivo peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers treated with multiple doses of efavirenz. The impact of efavirenz on hepatic metabolism in vivo was confirmed by significant changes in plasma 4ß-hydroxycholesterol and bilirubin levels and the area under the curve (AUC) of efavirenz. Induction of CYP2B6 mRNA expression correlated with the decrease in the AUC of efavirenz (r = 0.61; P = 0.036). Taken together, our results provide evidence that efavirenz exerts compartment-specific inductive capacity in vivo.

Impact of efavirenz on intestinal metabolism and transport: insights from an interaction study with ezetimibe in healthy volunteers.

Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection.

In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna.

Mesna and its dimer, dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters revealed saturable uptake by renal organic anion transporters OAT1, OAT3, and OAT4. Efflux transporters breast cancer resistance protein; multidrug and toxin extrusion 1 (MATE1); multidrug resistance proteins MRP1, MRP2, MRP4, and MRP5; and P-glycoprotein (Pgp) significantly reduced dimesna accumulation. Further investigation demonstrated that renal apical efflux transporters MATE1, MRP2, and Pgp were also capable of mesna efflux. Administration of OAT inhibitor probenecid to healthy subjects significantly increased combined mesna and dimesna plasma exposure (91% ± 34%) while decreasing the renal clearance due to net secretion (67.0% ± 12.7%) and steady-state volume of distribution (45.2% ± 13.4%). Thus, the kidney represents a significant sink of total mesna, whereas function of renal drug transporters facilitates clearance in excess of glomerular filtration rate and likely the presence of active mesna in the urine. Loss of renal transporter function due to genetic variability or drug-drug interactions may decrease the efficacy of chemoprotectants, increasing the risk of ifosfamide- and cisplatin-induced toxicities.

[Pharmacogenomics in routine medical care]. / Pharmakogenomik in der Praxis.

Pharmacogenomics investigates inherited differences in drug responses including beneficial and adverse reactions. While a considerable amount of evidence for genetic influences on drug responses has been accumulated within the last decade, predominantly in small studies, its value in routine therapy is still a matter of debate. The aim of this review is to discuss well established examples where pharmacogenomic techniques can improve routine treatment. Examples include genotyping of CYP2D6 in the context of antidepressant therapy, analysis of TPMT variants for the prediction of mercaptopurine-induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration and the SLCO1B1 variant in the context of statin-induced myopathies.

A piece in the puzzle of personalized medicine.

Predicting individual drug response based on inherited factors remains a major challenge. Some examples of significant contributions of single genetic variants to overall therapeutic success of drugs in complex diseases are currently emerging. For most compounds, however, multiple genetic and nongenetic factors will modify drug action. Comprehensive integration of these factors will determine the role of pharmacogenomics for personalized medicine.