Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms.

Raltegravir is a human immunodeficiency virus-1 (HIV-1) integrase strand transfer inhibitor metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). In this study, 30 subjects with a UGT1A1*28/*28 genotype (associated with decreased activity of UGT1A1) and 27 UGT1A1*1/*1 control subjects (matched by race, age, gender, and body mass index) received a single 400-mg dose of raltegravir after fasting. No serious adverse experiences were reported, and there were no discontinuations due to adverse experiences. The geometric mean ratio (GMR) (UGT1A1*28/*28 to UGT1A1*1/*1) and 90% confidence interval (CI) were 1.41 (0.96, 2.09) for raltegravir area under the concentration-time curve (AUC(0-infinity)), 1.40 (0.86, 2.28) for maximum plasma concentration (C(max)), and 1.91 (1.43, 2.55) for concentration at the 12-h time point (C(12 h)). No clinically important differences in time to maximum concentration (T(max)) or half-life were observed. Plasma concentrations of raltegravir are modestly higher in individuals with the UGT1A1*28/*28 genotype than in those with the UGT1A1*1/*1 genotype. This increase is not clinically significant, and therefore no dose adjustment of raltegravir is required for individuals with the UGT1A1*28/*28 genotype.

Sulfation pharmacogenetics: SULT1A1 and SULT1A2 allele frequencies in Caucasian, Chinese and African-American subjects.

Sulfotransferase (SULT) enzymes catalyze the sulfate conjugation of drugs, other xenobiotics, neurotransmitters and hormones. The genes for SULT1A1 and SULT1A2 contain common genetic polymorphisms that are associated with individual variations in levels of enzyme activity as well as variations in biochemical and physical properties. We set out to compare the frequencies of common SULT1A1 and SULT1A2 alleles in Caucasian, Chinese and African-American subjects. Allele frequencies for SULT1A1*1, *2 and *3 in 242 Caucasian subjects were 0.656, 0.332 and 0.012, respectively. Frequencies of those same alleles were significantly different in 290 Chinese subjects: 0.914, 0.080 and 0.006, respectively, as were frequencies in 70 African-American subjects: 0.477, 0.294 and 0.229, respectively. Ethnic variation in allele frequencies was also observed for SULT1A2, with frequencies in Caucasian subjects for SULT1A2*1, *2 and *3 of 0.507, 0.389 and 0.104; frequencies in Chinese of 0.924 and 0.076 with no *3 alleles observed; and, finally, in African-Americans frequencies of 0.637, 0.249 and 0.114, respectively. We also found that SULT1A1*2 and SULT1A2*2, the most common variant alleles for these two genes, were in positive linkage disequilibrium in all three populations studied, with D' values of 0.776 in Caucasian (P < 0.001), 0.915 in Chinese (P < 0.001) and 0.864 in African-American subjects (P < 0.001). These observations represent a step towards determining the possible functional implications for individual variations in sulfate conjugation of common genetic polymorphisms for SULT1A1 and SULT1A2.

Human 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 (PAPSS1) and PAPSS2: gene cloning, characterization and chromosomal localization.

Sulfae conjugation is an important pathway in the metabolism of a large number of exogenous and endogenous compounds. These reactions are catalyzed by sulfotransferase (SULT) enzymes that utilize 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as a sulfate donor. PAPS is synthesized from ATP and inorganic sulfate by PAPS synthetase (PAPSS). Two separate PAPSS cDNAs, PAPSS1 and PAPSS2, have been identified in human tissues. We have cloned and characterized the genes for human PAPSS1 and PAPSS2 to make it possible to study the pharmacogenomics of these enzymes. Both genes consisted of 12 exons with virtually identical exon-intron splice junction locations. All splice junctions conformed to the "GT-AG" rule. The total length of PAPSS1 was approximately 108 kb, while that of PAPSS2 was greater than 37 kb. The 5'-flanking region of PAPSS1 did not include a TATA box sequence near the site of transcription initiation, but PAPSS2 had a TATA motif located 21 bp upstream from the site of transcription initiation. Northern blot analysis showed that the major PAPSS1 and PAPSS2 transcripts were approximately 2.7 and 4.2 kb in length, respectively. PAPSS1 mapped to human chromosome band 4q24 while PAPSS2 mapped to 10q22-23 by fluorescence in situ hybridization analysis. Cloning and structural characterization of PAPSS1 and PAPSS2 will make it possible to perform molecular genetic and pharmacogenomic studies of these important enzymes in humans.

Elevated esterase activity in resistant tufted apple bud moth, Platynota idaeusalis (Walker) (Lepidoptera: Tortricidae).

1. Esterase activity in the tufted apple bud moth was measured spectrophotometrically by the hydrolysis of alpha-naphthyl acetate. 2. Resistant populations from both laboratory and field exhibited significantly greater esterase activity than did the respective susceptible populations. 3. The resistant laboratory population had significantly higher esterase activity than the resistant field population, suggesting that this field population contained a mixture of resistant and susceptible individuals.