MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity.

P-glycoprotein (PGP), the product of the multidrug resistance gene (MDR1), acts as an energy-dependent efflux pump that exports its substrates out of the cell. PGP expression is an important factor regulating absorption of a wide variety of medications. It has also been associated with intrinsic and acquired cross resistance to a number of structurally unrelated anticancer drugs. A single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T, was recently correlated with PGP protein levels and substrate uptake. Individuals homozygous for the T allele have more than four-fold lower PGP expression compared with CC individuals. As overexpression of PGP has been associated with altered drug absorption, therapy-resistant malignancies, and lower concentrations of HIV-1 protease inhibitors, this SNP may provide a useful approach to individualize therapy. To facilitate clinical application throughout the world, 1280 subjects from 10 different ethnic groups were evaluated for this SNP using the polymerase chain reaction-restriction fragment length polymorphism assay and the genotype and allele frequency for each group were ascertained. Marked differences in genotype and allele frequency were apparent between the African populations and the Caucasian/Asian populations (P < 0.0001). The Ghanaian, Kenyan, African American and Sudanese populations studied had frequencies of 83%, 83%, 84% and 73%, respectively, for the C allele. The British Caucasian, Portuguese, South-west Asian, Chinese, Filipino and Saudi populations had lower frequencies of the C allele compared to the African group (48%, 43%, 34%, 53%, 59%, and 55%, respectively). The high frequency of the C allele in the African group implies overexpression of PGP and may have important therapeutic and prognostic implications for use of PGP dependent drugs in individuals of African origin.

Gas chromatography mass spectrometry studies on biologically important 8-aminoquinoline derivatives.

Several substituted 8-aminoquinolines related to known antimalarial drugs have been studied by gas chromatography mass spectrometry. 5,6-Dihydroxy-8-aminoquinoline, a possible metabolite of Primaquine, can be detected by single ion monitoring after conversion to a trimethylsilyl ether derivative. The mass spectra obtained in this study indicate that there are certain ions which are characteristic of the trimethylsilyl ethers of hydroxylated 8-aminoquinolines and 5,6-dimethoxy-8-aminoquinolines. These compounds should thus be amenable to analysis if they were produced during in vivo metabolism studies. Using selected ion monitoring the derivatized compounds can be detected at submicrogram levels.

Age related differences in the disposition of acetanilide.

1 The metabolism of fifteen elderly hospital in-patients and fifteen young people was studied, using a gas chromatography mass spectrometer method. 2 The results suggest that there is no significant change in hepatic oxidation of acetanilide with age. 3 The concentrations of metabolites were however, significantly elevated in the older group. 4 These results illustrate the importance of the decline in renal function with age in the disposition of drugs.

A selected ion monitoring assay for primaquine in plasma and urine.

The antimalarial drug primaquine was analysed in plasma and urine by gas chromatography mass spectrometry, using a deuterated internal standard. After freeze-drying and extraction with trichloroethylene the sample plus internal standard was reacted with Tri Sil TBT (a 3:3:2 by volume mixture of trimethylsilylimidazole, N,O,-bis-(trimethylsilylacetamide and trimethylchlorosilane) and an aliquot injected into the gas chromatograph mass spectrometer. The gas chromatographic effluent was monitored at m/z 403 and m/z 406, the molecular ions of the bis-TMS ethers of primaquine and 6-trideuteromethoxy primaquine. Calibration curves were prepared from standards made up in plasma and urine. Data from the analysis of plasma and urine samples from a volunteer who ingested the equivalent of 45 mg primaquine are presented.

Blood quinidine levels and cardiac effects in white British and Nigerian subjects.

1 Differences between whites and blacks have been described in the incidence and patterns of cardiac disease and in electrocardiographic features. 2 The objective of the present study was to see if the ECG response to the same plasma and red blood cell quinidine concentration differed between whites and blacks. 3 It was found that following a standard single oral dose of quinidine both plasma and red blood cell quinidine concentrations tended to be lower in seven healthy white British subjects than in seven healthy Nigerians. 4 The change in QTc interval (delta QTc) after quinidine, however, tended to be greater in the white British subjects than in the Nigerians. 5 At a single plasma quinidine concentration the delta QTc tended to be higher in white British subjects than in Nigerians. 6 At a single blood cell quinidine concentration, delta QTc was significantly higher in British white subjects than in Nigerians. 7 The inter-ethnic differences found could be due to both environmental and genetic factors. Further work will be required to decide the relative importance of both these factors on plasma quinidine levels and QTc responses.

Diminished extractable spectrin in the erythrocytes of a patient with 'sporadic' hereditary spherocytosis.

A 51-year-old white man of Irish extraction was found to have apparent 'sporadic' hereditary spherocytosis with a reticulocyte count of 6%. Twelve of his 13 siblings were examined and found to be haematologically normal. The patient's erythrocytes were found to have a diminished amount of spectrin as compared to his siblings and to unrelated controls. It is suggested that the proband may represent either a new mutant or possibly double heterozygosity for two inherited biochemical variants of the red cell membrane skeleton which individually give no haematological abnormalities.

Total T lymphocytes in primary bronchial carcinoma.

Percentage and absolute levels of circulating T lymphocytes were measured in 48 patients with bronchial carcinoma. These were compared with control values from nine healthy adults and 19 age-matched patients with benign disorders. A further 20 patients who had been given postoperative immunotherapy after complete resection of bronchial carcinoma were also studied. There was no significant difference in the mean percentage T cells between the groups. Lymphopenia, however, was a feature of the bronchial cancer patients with metastatic disease. This resulted in a significant diminution of absolute T cells in this group. There is no evidence, with the technique employed in this study, of a total T-cell deficiency in early bronchial carcinoma.

Medicinal arsenic and internal malignancies.

A mortality analysis has been carried out on a cohort of patients given Fowler's solution (potassium arsenite) for periods ranging from 2 weeks to 12 years between 1945 and 1969. An excess of fatal and non-fatal skin cancer was apparent, but there was no overall excess mortality from cancer. Further analyses by site of cancer, dose level, and time from first exposure are also presented. A subset of patients were examined in 1969-70 for the presence of arsenical keratoses, hyperpigmentation and skin cancer. About half the patients had one or more of these signs. Although the cancer mortality of this entire subgroup was similar to the expected value, all the cancer deaths occurred in patients with prior signs of arsenicism. These data suggest that while any excess of internal malignancy due to the use of Fowler's solution is small or non-existent, there may be a susceptible subgroup which can be identified from dermatological manifestations.