Inter- and intra-subject variability in ethanol pharmacokinetic parameters: effects of testing interval and dose.

Calculation of a blood alcohol concentration (BAC) at the time of an offence by forward or back-extrapolation, using population average values for ethanol pharmacokinetic parameters or a single estimate of individual specific parameters, ignores the possibility of inter- and intra-subject variability. In order to estimate inter- and intra-subject variability in the elimination rate and absorption rate, BAC was measured over time in 12 male volunteers on 4 occasions. Subjects received 0.44 g kg(-1) body weight of ethanol on the first study day, and 0.70 g kg(-1) body weight on subsequent study days 1, 11 and 12 weeks later, to enable comparisons in variability over short and long time periods and when the same or different doses were administered. Evidence of both inter- and intra-subject variability was found, with inter-subject variability substantially smaller than intra-subject variability when the dose varied. Forensically important differences in pharmacokinetic parameters were observed within individuals between occasions. These findings could have an important impact on medico-legal issues related to ethanol pharmacokinetics.

Velafermin improves gastrointestinal mucositis following irinotecan treatment in tumor-bearing DA rats.

Mucositis is a common, costly and unpleasant side effect of cancer chemotherapy and radiotherapy. Velafermin (FGF-20) has shown the potential to reduce these side effects. Irinotecan is a chemotherapeutic agent which is commonly used in solid tumors, and causes GI mucositis manifested by severe diarrhea. Therefore the primary aim of this study was to investigate whether velafermin reduces the GI mucositis induced by irinotecan. The secondary aim was to test varying schedules of administration of velafermin. Groups of tumor-bearing DA rats (6 per group) were treated with varying doses (4, 8 or 16 mg/kg) of velafermin intraperitoneally either prior to, prior to and during, or after chemotherapy treatment. Rats received a single dose of 200 mg/kg irinotecan intraperitoneally. Rats were monitored closely for the incidence and severity of diarrhea and mortality before being killed 192 h following treatment. Mortality, diarrhea and histopathology were assessed throughout the gastrointestinal tract. Severe or moderate diarrhea occurred in approximately 40% of rats treated with irinotecan alone. This was associated with a 50% mortality rate 96 h following chemotherapy. Velafermin administered at 16 mg/kg prior to irinotecan improved gastrointestinal mucositis as measured by reduced diarrhea and mortality following irinotecan chemotherapy in the DA rat. Rats that received velafermin prior to, or prior to and during irinotecan treatment did develop severe or moderate diarrhea, however it occurred later, in fewer rats and was not associated with mortality. Other dosing regimens were not as effective. This has important implications for the use of velafermin in GI mucositis in humans, and should be further studied.

Chemotherapy-induced diarrhea is associated with changes in the luminal environment in the DA rat.

The microflora of the gastrointestinal tract (GIT) are a complex ecosystem, performing a number of beneficial functions. Irinotecan causes both early and late diarrhea, the latter possibly caused, in part, by changes in the microflora of the GIT. Female DA rats were given atropine subcutaneously, prior to a single 200 mg/kg intraperitoneal dose of irinotecan. Animals were monitored for diarrhea and killed at 30 and 60 mins, 2, 6, 12, 24, 48, and 72 hrs after chemotherapy administration. Control rats received no treatment. Fecal samples and stomach, jejunum, and colon samples were collected and stored at -70 degrees C until required. Standard microbiological culture techniques were used to grow and isolate the flora. Biochemical tests were used to identify the bacteria. The level of growth was noted for relative comparison between time points and graded accordingly. Early diarrhea was observed in the rats from 2-6 hrs after treatment, after which time the diarrhea resolved. Late onset diarrhea was apparent 72 hrs after treatment. Changes were seen in the flora of the stomach, jejunum, colon and feces. The majority of microflora changes were seen 6, 12, and 24 hrs after treatment, with a relative increase or decrease in the presence of bacteria in comparison with control rats. In some rats bacteria were not observed at all time points, and different bacteria not seen in control animals were identified in rats treated with irinotecan. These changes were observed up to 72 hrs after treatment. In conclusion, irinotecan treatment causes changes in the flora of the stomach, jejunum, colon, and feces of rats and is associated with the development of diarrhea. These changes in flora may have systemic effects and in particular may contribute to the development of chemotherapy-induced mucositis.