Melih O. Babaoglu

Functional impact of CϒP2C9*5, CϒP2C9*6, CϒP2C9*8, and CϒP2C9*11 in vivo among black Africans

Previous data indicate that the urinary losartan/E‐3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo. The functional impact of CYP2C9*5, *6, *8, and *11 polymorphisms in vivo has not been investigated previously in humans.

Molecular Diagnosis and Clinical Characterization of Pseudohypoparathyroidism Type-Ib in a Patient With Mild Albright’s Hereditary Osteodystrophy-Like Features, Epileptic Seizures, and Defective Renal Handling of Uric Acid

We describe a patient who presented with epileptic seizures unresponsive to anticonvulsive treatment. Laboratory investigations demonstrated epileptiform seizure activity in the brain but also revealed severe hypocalcemia, hyperphosphatemia, and elevated serum parathyroid hormone. In addition, the patient showed a reduced serum level of 25-[OH]-vitamin D. The diagnosis of pseudohypoparathyroidism type-Ib (PHP-Ib) was made based on these clinical findings and upon identification of a 3-kb deletion within the STX16 locus, a genetic defect frequently associated with autosomal dominant PHP-Ib. This mutation was also present in the patients unaffected mother and her affected sister. Despite the molecular diagnosis of PHP-Ib, which is characterized by parathyroid hormone resistance in the absence of Albrights hereditary osteodystrophy (AHO), the patient had a round face, slightly short stature, and short fourth metacarpals, which were consistent with mild AHO. The patient and her affected sister, who lacked AHO-like features, showed reduced serum levels of uric acid and increased fractional excretion of uric acid, a finding that was reported only once previously for PHP-Ib. Unlike the previous report, the fractional uric acid excretion and serum uric acid levels returned to normal in our patient and her sister after 3 months of treatment period. These findings underscore several important points with respect to the pathogenesis and clinical presentation of PHP-Ib. Furthermore, the findings in the index case present interesting novel aspects, including a previously undescribed coexistence of the 3-kb STX16 deletion and AHO-like features and a clinical course complicated by concomitant 25-[OH]-vitamin D deficiency, which may have resulted, at least partly, from long-term use of antiepileptic drugs.

Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5‐hydroxytryptamine type 3 antagonists

Resistance to antiemetic treatment with 5‐hydroxytryptamine type 3 (5‐HT3) receptor antagonists is still a major problem resulting in patient discomfort and poor compliance to chemotherapy. We hypothesized that clinical resistance to 5‐HT3 antagonists is associated with the single‐nucleotide polymorphism (3435C > T) in the gene that codes for the drug efflux transporter adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1).

Capecitabine-Induced Severe Hypertriglyceridemia: Report of Two Cases

Objective: To report 2 cases of severe hypertriglyceridemia associated with the use of oral capecitabine. Case Summaries: The first patient was a 73-year-old woman with metastatic breast carcinoma who received capecitabine 2500 mg/m2/day in 2 divided doses for 2 weeks followed by a one week rest period. The baseline triglyceride level was 324 mg/dL; after 2 cycles of capecitabine, levels increased to 916 mg/dL. Although lipid-lowering treatment was initiated, triglyceride levels peaked at 1782 mg/dL by the end of the seventh cycle. Eight weeks after capecitabine treatment was stopped, triglyceride levels decreased to 118 mg/dL. The second patient was a 59-year-old man with metastatic colorectal carcinoma who was placed on capecitabine treatment at a dosage of 2500 mg/m2/day in 2 divided doses for 2 weeks followed by a one week rest period. The baseline triglyceride level was 244 mg/dL; levels peaked at 1455 mg/dL at the end of the fifth cycle. Capecitabine treatment was discontinued due to disease progression, and triglyceride levels decreased to 154 mg/dL after 11 weeks. Discussion: The most frequently reported adverse effects of capecitabine are gastrointestinal and hematologic effects and palmar-plantar erythrodysesthesia. Drug-induced hyperlipidemia may appear more readily in individuals with hereditary lipoprotein lipase deficiency because decreased lipoprotein lipase activity might make these individuals more susceptible to a rise in triglyceride levels. The Naranjo probability scale indicated a probable relationship between capecitabine and severe hypertriglyceridemia. Conclusions: Capecitabine should be prescribed with care, especially in patients with preexisting hypertriglyceridemia. The question of whether capecitabine actually causes hypertriglyceridemia needs careful consideration, and the possible mechanism by which it may cause this adverse effect requires further investigation.

Multidrug resistance in patients undergoing resective epilepsy surgery is not associated with C3435T polymorphism in the ABCB1 (MDR1) gene.

PURPOSE The C3435T polymorphism in the gene coding for P-glycoprotein (ABCB1) has been correlated with drug resistance in patients with epilepsy. However, replication studies have revealed conflicting results and the reason for this is not clear. We investigated the frequency of C3435T polymorphism in epileptic Turkish patients who underwent resective epilepsy surgery and compared our results with healthy controls. METHODS DNA samples were obtained from 100 healthy controls and 89 consecutive adult patients who underwent resective brain surgery due to refractory seizures at our epilepsy center. Genotypes for the C3435T polymorphism were determined by PCR and restriction analysis. RESULTS Comparison of drug-resistant patients and healthy controls revealed no significant difference in allele frequency (C vs. T; chi(2)=0.015, p=0.90) and genotype frequency (chi(2)=2.05, p=0.36). The findings in the pure hippocampal sclerosis (HS) group (n=73) were not significantly different from control subjects, either (allele frequency: chi(2)=0.29, p=0.59; genotype frequency: chi(2)=2.14, p=0.34). CONCLUSIONS Our findings failed to prove an association between C3435T polymorphism and drug resistance in a sample of Turkish patients with refractory epilepsy who underwent resective brain surgery.

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype-phenotype correlation in childhood.

PurposeLansoprazole, a cytochrome P450 2C19 (CYP2C19) substrate, has been widely used in children to manage acid-related diseases. CYP2C19 exhibits marked genetic polymorphisms, and distribution of these polymorphisms varies among different ethnic groups. There is limited data regarding the use of probe drugs for determining CYP2C19 activity in children. The aim of this study was to evaluate lansoprazole as an in vivo phenotyping probe for assessing CYP2C19 activity in children.MethodsThe CYP2C19*2, *3, and *17 variants were determined in 244 children. Three hours after a single oral dose of lansoprazole (n = 94) or omeprazole (n = 19), plasma lansoprazole and 5-hydroxy lansoprazole or omeprazole and 5-hydroxy omeprazole concentrations were analyzed by high-performance liquid chromatography.ResultsThe CYP2C19*17 was the most frequent variant allele (24.4%). The group of patients with CYP2C19*17*17 genotype had a 70% lower (p < 0.05) mean lansoprazole plasma concentration compared with the CYP2C19*1*1 genotype group, whereas the CYP2C19*2*2 group had 6.9-fold higher (p < 0.01) mean lansoprazole plasma concentration. Lansoprazole metabolic ratios (lansoprazole/5-hydroxy-lansoprazole) were found to be significantly lower in the *17*17 [mean ± standard deviation (SD); 2.8 ± 2.1] group and higher in the *2*2 group (63.5 ± 12.2) compared with that of the *1*1 genotype group (6.1 ± 4.5).ConclusionAccording to our results from a Turkish pediatric population, lansoprazole is a suitable probe drug for phenotyping CYP2C19. The CYP2C19*2 and *17 variants should be taken into consideration in predicting the clinical outcome of therapy with lansoprazole in the pediatric population.

Tamoxifen Inhibits Cytochrome P450 2C9 Activity in Breast Cancer Patients

Abstract Tamoxifen has been reported to potentiate the anticoagulant effect of warfarin and also to increase the plasma level of phenytoin, which are mainly metabolized by CYP2C9. The aim of this study was to determine the influence of tamoxifen on CYP2C9 activity in vivo in humans. Thirteen breast cancer patients who would start tamoxifen following cytotoxic chemotherapy were enrolled in the study. A single oral dose of 25 mg losartan was given to the patients 2 days before and 2 weeks after starting tamoxifen therapy. Losartan and E3174 in 8-hour urine samples were measured by HPLC. Tamoxifen significantly increased the average urinary losartan/E3174 ratio from 0.73 (CI95%=0.15-2.30) to 1.66 (CI95%=0.68-5.20), after 2 weeks of treatment (p=0.002). Tamoxifen inhibited CYP2C9 activity in breast cancer patients within two weeks of its administration. The inhibition of CYP2C9 activity may be a possible explanation for the drug-drug interaction of tamoxifen with CYP2C9 substrates.

Frequency and enzyme activity of the butyrylcholinesterase K-variant in a Turkish population

ObjectiveAmong variants of the butyrylcholinesterase gene (BChE), the K-variant causing Ala539Thr substitution is the most common one associated with about one-third reduction in the enzyme activity. This study aimed to detect the frequency of the K-variant allele in a Turkish population sample and also to evaluate how the plasma BChE activity was influenced by this variant.MethodsPatients administered for elective surgery (n=77) were examined for the presence of the K allele. The enzyme activity was determined in plasma.ResultsThe K-variant of BChE is a common allele with a frequency of 0.266 (CI95% 0.196–0.336) in our sample from a Turkish population. Mean enzyme activity in subjects homozygous for the K-variant was about 40% lower than other subjects.ConclusionThe frequency of the BChE K-variant was significantly higher in a Turkish population than those reported for other populations and it is associated with a diminished enzyme activity.

Improved anti-emetic efficacy of 5-HT3 receptor antagonists in cancer patients with genetic polymorphisms of ABCB1 (MDR1) drug transporter.

Chemotherapy‐induced nausea and vomiting (CINV) remains a major adverse effect decreasing quality of life in patients with cancer. Genetic variations among patients may be responsible for part of the lack of efficacy of anti‐emetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect anti‐emetic treatment with 5‐HT3 receptor antagonists. Patients (n = 239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Anti‐emetic responses were recorded daily. The primary end‐point of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR‐RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT, p = 0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p = 0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p = 0.021). Subjects carrying homozygous variant alleles together (TT‐TT‐TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT‐TT‐TT versus 47.1% in other genotypes, p = 0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p = 0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti‐emetic response to 5‐HT3 receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the anti‐emetic efficacy of 5‐HT3 antagonists.

Disposition of a CYP2C9 Phenotyping Agent, Losartan, Is Not Influenced by the Common 3435C > T Variation of the Drug Transporter Gene ABCB1 (MDR1)

Losartan is oxidized to E3174 by cytochrome P450 2C9 (CYP2C9); it has been suggested as a useful probe drug for CYP2C9 activity. It has also been shown to be a substrate for the drug-efflux transporter ATP-binding cassette sub-family B member 1 (ABCB1, MDR1). Both CYP2C9 and ABCB1 genes are polymorphic. The aim of the study was to determine if losartan disposition was influenced by the 3435C > T polymorphism of ABCB1 in healthy persons. These participants (n = 58) whose CYP2C9 genotypes and phenotypes were determined previously were genotyped for 3435C > T polymorphism in ABCB1. The concentrations of losartan and E3174 were compared across genotypes for ABCB1 3435C > T variation. For persons with the ABCB1 3435 CC, CT, TT genotypes, the concentrations (microM, means +/- S.D.) of neither losartan (1.76 +/- 0.87, 1.68 +/- 0.84 and 1.80 +/- 0.85, respectively, P = 0.70) nor E3174 (2.97 +/- 2.49, 2.53 +/- 2.09 and 3.18 +/- 2.75, respectively, P = 0.65) were significantly different. These results suggest that ABCB1 3435C > T polymorphism does not have any influence on losartan disposition. Therefore, ABCB1 3435C > T polymorphism is probably not a confounding factor in the prediction of CYP2C9 activity by using losartan as a probe agent.