5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

Background: Methotrexate (MTX) is the most used drug for the treatment of rheumatoid arthritis (RA) although outcome differs among patients. Aim: To evaluate whether polymorphisms in pharmacokinetic genes are associated with outcome in RA patients receiving MTX. Patients & methods: We analyzed 28 SNPs in SLC19A1/RFC1, ABCB1, FPGS and GGH genes. Results: We studied 194 RA patients receiving MTX monotherapy. Two FPGS SNPs, rs10987742 and rs10106, were associated with response (p = 0.033 and p = 0.041, respectively). The FPGS rs10106 variant was also associated with MTX survival (p = 0.005) and toxicity (p = 0.021). Three ABCB1 SNPs, rs868755, rs10280623 and rs1858923, were associated with toxicity (p = 0.025, p = 0.048 and p = 0.031, respectively). Conclusion: FPGS and ABCB1 genetic variants can influence the outcome in RA patients receiving MTX monotherapy.

Severe irinotecan‐induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side‐effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan‐metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss‐of‐function allele in the toxicity profile of these patients. Three‐hundred and eight metastatic colorectal cancer patients treated with an irinotecan‐containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia (P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan‐induced toxicity.

The link between human immunodeficiency virus/highly active antiretroviral therapy (HAART)—associated lipodystrophy syndrome (HALS) and the use of thymidine analogues has been well established. However, to our knowledge, no relationship has been proven between intracellular levels of stavudine (d4T) and HALS. We measured peripheral blood mononuclear cell intracellular levels of d4T-triphosphate (TP) in patients who were receiving d4T as part of their antiretroviral regimens. d4T-TP levels were determined by a validated liquid chromatography-tandem mass spectrometry assay method. The diagnosis of HALS was made in accordance with the criteria of a lipodystrophy severity grading scale. The Student t test, Pearson correlations, 1-way analysis of variance with Bonferroni correction, and stepwise logistic regression were used for statistic analyses. This was a cross-sectional study. There were 33 patients: 17 with HALS and 16 without HALS. The median concentration of d4T-TP for patients with HALS was 20.60 femtomoles (fmol)/1 × 10⁶ cells (interquartile range [IQR], 14.90–26.92 fmol/1 × 10⁶ cells) and for patients without HALS was 13.85 fmol/1 × 10⁶ cells (IQR, 8.65–20.15 fmol/1 × 10⁶ cells) (P = .013). The median d4T-TP intracellular level in patients who had developed an AIDS-defining condition was 22.50 fmol/1 × 10⁶ cells (IQR, 15.80–27.37 fmol/1 × 10⁶ cells) and in those who had not was 14.40 fmol/1 × 10⁶ cells (IQR, 10.80–20.40 fmol/1 × 10⁶ cells) (P = .037). There were no statistically significant differences in d4T-TP intracellular levels with respect to the presence of metabolic syndrome, the clinical form of HALS (pure lipoatrophic vs mixed), the degree of facial lipoatrophy, the presence of hepatitis C virus infection, and the pair of nucleosides in HAART. d4T-TP levels correlated only with cumulative d4T exposure in time and dose. d4T-TP intracellular levels were independently associated with HALS (odds ratio, 1.58; 95% confidence interval, 1.08–2.32; P = .019). Intracellular levels of d4T-TP are strongly associated with the development of HALS.