Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients.

This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan.

In vitro study of the percutaneous absorption of four aromatic amines using hairless rat skin.

Using hairless rat skin maintained in a Franz diffusion cell, the percutaneous penetration of four aromatic amines: para-chloroaniline (PCPA), meta-trifluoromethylaniline (mTFMA), dichloro-3,4-aniline (3,4-DCA) and dichloro-3,5-aniline (3,5-DCA) were studied. The purpose of the studies was to determine the permeation parameters (rate of permeation, permeability rat constant) in order to compare the rate of absorption of the four amines. The results show that the four amines penetrate significantly across the skin, but with different rates. 10 h after in vitro application (2 mg/cm2), the extent of permeation was PCPA >> mTFMA > 3,4-DCA > 3,5-DCA.