Purpose: ABT-751is anoral antimitotic agent that binds to the colchicine site on h-tubulin. A phase 1study was conducted to determine the maximum tolerated dose and toxicities of ABT-751in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Study Design: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m 2 (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m 2 (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). Results: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m 2 , with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala 185

This study utilized cytochrome P450 2D6 (CYP2D6) genotypes to explain variability of desipramine pharmacokinetics in a cohort of non-poor metabolizer individuals. In an interaction study utilizing desipramine as a probe, genotyping for the CYP2D6*3, *4, *5 and *6 alleles was used to screen out CYP2D6 poor metabolizers. Individuals were categorized according to these and additional alleles (CYP2D6*2, *9, *10, *17, *41 and x2). Genotypes of individuals heterozygous for two or three of *2, *17 and *41 alleles were confirmed by molecular haplotyping. Pharmacokinetic parameters of desipramine were analysed according to CYP2D6 category. Molecular haplotyping was necessary to definitively categorize four of 16 individuals. A subject who had unusually high plasma elimination half-time, exposure and metabolic ratios carried an intermediate metabolizer (IM) *9 allele in combination with a non-functional allele. This combination has a population frequency of less than 1 : 200. Individuals with *1/*1, *1/*2 and *2/*2 genotypes had lower than average plasma elimination half-time, exposure and metabolic ratios. For desipramine, additional genotyping of CYP2D6 IM alleles helped define subgroups of the CYP2D6-positive cohort. This suggests that genotyping for IM alleles will aid in interpretation of clinical trials involving CYP2D6 substrates. Due to the diversity of IM alleles, molecular haplotyping may be necessary to fully characterize CYP2D6 genotype-phenotype relationships.

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ABSTRACT:Cytochrome P450 2D7 (CYP2D7) has long been considered a pseudogene. A recent report described an indel polymorphism (CYP2D7 138delT The cytochrome P450 2D (CYP2D) locus on chromosome 22 comprises three highly homologous genes, CYP2D6, CYP2D7, and CYP2D8. CYP2D6 metabolizes a wide range of commonly prescribed drugs, and genetic polymorphisms in the corresponding CYP2D6 gene are recognized as important contributors to interindividual variability of pharmacokinetics and, in some cases, drug efficacy or safety (reviewed in Bernard et al., 2006). Relationships between genotype and metabolizer phenotype for CYP2D6 are well characterized, with individuals classified as poor, intermediate, extensive, or ultrarapid metabolizers based on genotype. The ultrarapid metabolizer phenotype is usually attributed to an amplification of the functional CYP2D6 gene (Løvlie et al., 2001). However, not all ultrarapid metabolizer phenotypes are explained by CYP2D6 gene duplications, suggesting the contribution of other, yet unknown factors (Løvlie et al., 2001). In addition to the functional CYP2D6, the CYP2D locus contains two nonfunctional pseudogenes, CYP2D7 and CYP2D8. CYP2D8 has multiple sequence differences relative to CYP2D6 that render it nonfunctional (reviewed in Zanger et al., 2004). In contrast, the open reading frame of CYP2D7 is disrupted only by a single base insertion within exon 1 (Kimura et al., 1989). A functional CYP2D7 gene that produces active enzyme might result from either deletion of the extra nucleotide or replacement of exon 1 by gene conversion and could contribute to the rapid-metabolizer phenotype in CYP2D6 amplification-negative individuals. For example, deletion of nucleotide 138T could restore CYP2D7 enzyme expression. Løvlie et al. (2001) examined this hypothesis by genotyping 17 CYP2D6 duplicationnegative ultrarapid or extensive metabolizers at this site, but all individuals were homozygous for the wild-type nonfunctional CYP2D7 allele.)In a recent report, the 138delT polymorphism was observed in 6 of 12 samples in an Indian population (Pai et al., 2004). CYP2D7 protein translated from a brain-specific, alternatively spliced transcript was detected in samples containing the 138delT polymorphism. Protein expressed from the CYP2D7 variant transcript showed activity that differed from CYP2D6 in preferentially converting codeine to morphine rather than norcodeine. The reported high frequency of the CYP2D7 138delT variant, and the possibility that the resulting enzyme could be responsible for conversion of codeine to morphine in the human brain, suggested an important role for this variant in drug disposition. Furthermore, variability in expression of CYP2D in the brain may be a factor for variability in response to other psychoactive drugs that are CYP2D6 substrates.Following on the above report, , using a CYP2D7-specific assay, did not detect the CYP2D7 138delT variant in their sample panel comprising Caucasian Americans (n ϭ 109), African Americans (n ϭ 112), Asian Americans (n ϭ 43), Indians (...

BACKGROUND Polymorphisms within cytochrome P450 2D6 (CYP2D6) result in different metabolizer phenotypes, but some discordance suggests the possibility of additional unknown alleles or factors contributing to metabolism. A recent study showed a high frequency frameshift‐causing deletion, CYP2D7 138delT, which converted the CYP2D7 pseudogene to a functional gene within the brain.1 The high frequency of the deletion and the resulting CYP2D7 expression could have important implications for brain‐specific metabolism of psychoactive substances. Our goal was to determine the frequency of this deletion in a larger ethnically diverse population. METHODS The CYP2D7 138delT genotypes for 163 Caucasians, 95 East Asians, 50 South Asians, 68 Hispanic Latinos, and 68 African Americans were determined by Pyrosequencing. RESULTS The 138delT allele was observed at a frequency of 1.0% in East Asians and 0.74% in Hispanic Latinos. The deletion was not observed in the other ethnic populations. CONCLUSIONS The very low frequency of the CYP2D7 138delT polymorphism in our panel is in contrast to the high frequency (50%) reported in the Indian population.1 Our results suggest that CYP2D7 138delT is unlikely to be highly relevant for population variation of pharmacokinetics or drug response. Clinical Pharmacology & Therapeutics (2005) 79, P42–P42; doi: