Volume 29, Issue 2

Carbamazepine (CBZ) is a first-line widely used anticonvulsant. It has a narrow therapeutic index and exhibits considerable interindividual and interethnic variability in clinical efficacy and adverse drug reactions including potentially life-threatening hypersensitivity reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The most important pharmacogenetic finding is related to the association of CBZ-induced hypersensitivity with human leukocyte antigens ( HLA class I and II alleles). Moreover, genotyping for HLA-B*15:02 allele is required prior to initiating CBZ in Asians and Asian ancestry patients, demonstrating the usefulness of biomarkers to avoid adverse drug reactions. On the other hand, in order to explain the differences in the clinical response to CBZ, genetic polymorphisms in phase I ( CYP3A4, CYP3A5 and EPHX1 ) and phase II ( UGT2B7 ) metabolising enzymes have been assessed; additionally, the influence of transporters ( ABCB1 and ABCC2 ), receptors ( PXR ) and other drug targets (voltage- gated Na+ channels) in CBZ clinical response has been evaluated. To date, these studies are controversial and require further investigations to clarify the functional role of these polymorphisms as potential biomarkers in regard to CBZ therapy.

Drug metabolizing enzymes (DMEs) play a major role in the metabolism and final elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Most studies on the pharmacogenetics (PGx) of DMEs and its influence on interindividual variability have been conducted in Western countries. Middle Easterners, however, may have a different genetic makeup and may be exposed to different environmental factors when compared with their Western counterparts. Thus, results obtained in Western populations cannot be extrapolated to the population of the Middle East, and it is important to examine and document PGx differences and influences within the Middle Eastern population as there have been very little published data from this region. Herein, we provide an update on the genetic polymorphisms of DMEs that were studied in Lebanon and their impact on drug toxicity and efficacy. It is hoped that with more time, additional funds, and perseverance, the PGx of DMEs in Lebanon picks up and becomes closer in quantity and quality to that in the West.

Background: Most identified drug transporters belong to the ATP-binding cassette (ABC) and solute carrier (SLC) families. Recent research indicates that these transporters play an important role in the absorption, distribution and excretion of drugs, and are involved in clinically relevant drug-drug interactions for systemic drugs. However, very little is known about the role of drug transporters in human skin, especially in the disposition of topically applied drugs, and their involvement in drug-drug interactions. The aim of this work was to characterize the ABC transporters in human skin. Methods: Expressions of ABCB1 multidrug resistance protein 1 (MDR1) also known as P-gp, ABCC1 and ABCC2 multidrug resistance-associated protein 1 and 2 (MRP1 and MRP2), and ABCG2 brest cancer resistance protein (BCRP) in human skin tissues were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). The modulations of ABCB1 and ABCC1 expressions were analyzed after ex vivo treatment of human skin with rifampicin and dexamethasone. The localization of the major transporter MRP1 in human skin was analyzed by immunohistochemistry. Finally, functional analysis of MRP1 in human skin was performed using different specific substrates and inhibitors. Results: The expressions of ABCB1, ABCC1, ABCC2 , and ABCG2 were all detected in human skin, of which the expression of ABCC1 was considered the most important. The comparison of human skin with human hepatocytes and kidneys shows that the expression of ABCC1 increased 15-fold in skin than in hepatocytes. Immunohistochemistry revealed marked expressions of MRP1 within the hair follicle, sweat gland and muscle, as well as moderate expression in the basal epidermis. Functional analysis demonstrated that the skin absorptions of rhodamine 123, [ 3 H]-vinblastine, and [ 3 H]-LTC4 were markedly decreased in the presence of MRP1 inhibitors (verapamil and MK571), thus supporting the role of MRP1 in the uptake of compounds from the epidermal compartment as well as their secretion into the bloodstream and sweat ducts. Conclusions: The present findings are the first to demonstrate the involvement of MRP1 in drug uptake in human skin.

Background: The purpose of this study is to identify the effect of binary and ternary combinations of anti-HIV protease inhibitors (PIs) on the expression of metabolizing enzyme (CYP3A4) and efflux transporters [multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)] in a model intestinal cell line (LS-180). Methods: LS-180 cells were treated with various combinations of PIs (amprenavir, indinavir, saquinavir and lopinavir), and the mRNA expression levels of metabolizing enzyme and efflux transporters were measured using quantitative reverse transcription polymerase chain reaction. The alteration of gene expression was further correlated to the expression of nuclear hormone receptor PXR. Uptake of fluorescent and radioactive substrates was carried out to study the functional activity of these proteins. Cytotoxicity and adenosine triphosphate (ATP) assays were carried out to measure stress responses. Results: Binary and ternary combinations of PIs appeared to modulate the expression of CYP3A4, MRP2, P-gp and BCRP in a considerable manner. Unlike the individual PIs, their binary combinations showed much greater induction of metabolizing enzyme and efflux proteins. However, such pronounced induction was not observed in the presence of ternary combinations. The observed trend of altered mRNA expression was found to correlate well with the change in expression levels of PXR. The gene expression was found to correlate with activity assays. Lack of cytotoxicity and ATP activity was observed in the treatment samples, suggesting that these alterations in expression levels were probably not stress responses. Conclusions: In the present study, we demonstrated that combinations of drugs can have serious consequences toward the treatment of HIV infection by altering their bioavailability and disposition.

Background: Raloxifene is a selective estrogen receptor (ER) modulator (SERM) used for the treatment of osteoporosis. However, its efficacy and also its safety vary greatly among treated patients, and it might be influenced by the individuals’ genetic background. As the receptor activator of the nuclear factor κB (RANK) ligand (RANKL)/RANK/osteoprotegerin (OPG) system is essential for osteoclastogensis and Wnt signaling pathway for osteoblastogenesis, we decided to evaluate the raloxifene treatment in regard to selected polymorphisms in key genes of these two main bone regulatory pathways. Methods: Fifty-six osteoporotic postmenopausal women treated with raloxifene were genotyped for 11 polymorphisms located in six genes: -290C>T, -643C>T, and -693G>C in tumor necrosis factor receptor superfamily member 11 ( TNFSF11 ), +34694C>T, +34901G>A, and +35966insdelC in tumor necrosis factor receptor superfamily member 11A ( TNFRSF11A ), K3N and 245T>G in tumor necrosis factor receptor superfamily member 11B ( TNFRSF11B ), A1330V in LRP5 , I1062V in LRP6 , and -1397_-1396insGGA in SOST . For evaluation of treatment efficacy, bone mineral density (BMD) and biochemical markers of bone turnover were measured. Results: One-year change in total hip BMD was associated with +34901G>A in TNFRSF11A (p=0.040), whereas, for lumbar spine BMD, the association was shown for -1397_-1396insGGA in SOST (p=0.015). C-terminal crosslinking telopeptides of type I collagen (CTX) concentrations showed significant association with -643C>T single nucleotide polymorphism (SNP) in TNFSF11 (p=0.049) and +34694C>T in TNFRSF11A (p=0.022). No other association was found between 1-year change in BMDs or biochemical markers and the studied SNPs. Conclusions: We have shown that, in postmenopausal osteoporotic women treated with raloxifene, the efficacy of raloxifene treatment might be influenced by +34901G>A in TNFRSF11A gene and -1397_-1396insGGA in the SOST gene as well as -643C>T in TNFSF11 gene and +34694C>T in TNFRSF11A gene. However, these findings need additional functional and clinical confirmation for potential pharmacogenetic use in the future.

Background: This was a randomized, open-label, three-way crossover study to assess the effects of AST-120 (an orally administered spherical carbon adsorbent acting in the gastrointestinal tract without systemic circulation) on the single-dose pharmacokinetics of metoprolol in an extended-release formulation (metoprolol ER) in healthy volunteers. Methods: A total of 34 subjects were singly administered metoprolol ER alone (A), and metoprolol ER in combination with AST-120 simultaneously (B) and 1 h later (C). Results: The total exposure was more significantly reduced in both treatments B and C than that in treatment A; the geometric mean ratios of area under the curve extrapolated to infinity (AUC 0–∞ ) for B/A and C/A were reduced by approximately 30% in both treatments B and C. Maximum observed plasma concentration ( C max ) of metoprolol in treatment B significantly decreased, whereas C max in treatment C was slightly decreased. AST-120 treatment was unlikely to affect apparent first-order terminal elimination half-life ( T 1/2 ) of metoprolol significantly. Reduction in heart rate and blood pressure readings were similar across the treatment periods. Coadministration of AST-120 and metoprolol ER was safe and was well tolerated. Conclusions: Because AST-120 reduced gastrointestinal absorption of metoprolol ER, careful monitoring of heart rate and blood pressure is recommended in coadministration of AST-120 with metoprolol ER.

Background: Drug-induced liver enzyme abnormalities may indicate hepatic injury. Antipsychotic drugs also may cause increase in the liver enzymes and serum bilirubin levels. The present report evaluates the case of a patient with risperidone-associated hepatocellular damage. Case summary: A 19-year-old Caucasian man was admitted to the Department of Psychiatry with paranoid schizophrenia and risperidone was administered in a gradually increasing dose up to 8 mg/day. After 3 weeks of treatment, he experienced asthenia and weight loss. The level of aspartate aminotransferase was 283 IU/L (normal: <30 IU/L), and the alanine aminotransferase level was 778 IU/L (normal: <36 IU/L). Treatment with risperidone was immediately discontinued. Six days after drug withdrawal, the alanine aminotransferase level fell more than 50%, and a complete return to normalcy was seen within 2 months. Results: In the present case, a possible causal association between risperidone and hepatocellular damage has been observed due to the temporal relationship between the administration of the drug and the onset of hepatic abnormalities, and a following rapid recovery after stopping the drug. As the hepatic damage could be related to the plasma concentration of risperidone which is highly influenced by the hepatic enzyme CYP2D6, the patient was genotyped for CYP2D6 . He was classified as homozygous wild type for CYP2D6 . Conclusions: The risk for developing hepatotoxicity during risperidone therapy cannot be supported by the patient CYP2D6 genotype. In clinical practice, it may be recommended to obtain baseline liver function tests before starting risperidone and regular screening for liver enzyme changes during therapy.