Michel Lavit

Influence of Simulated Weightlessness on the Oral Pharmacokinetics of Acetaminophen as a Gastric Emptying Probe in Man: A Plasma and a Saliva Study

This study evaluated the effect of simulated weightlessness on gastric emptying, using acetaminophen as a probe and −6° head‐down bed rest to simulate zero gravity. Eighteen volunteers were given 1 g of acetaminophen orally before the bed rest and at days 1, 18, and 80. Cmax, tmax, AUC0‐∞, AUC0‐t, and t1/2 were calculated for plasma and saliva. The plasma Cmax showed a significant increase (10.43 μg/mL [day 1] to 14.74 μg/mL [day 80]), while tmax significantly decreased (1.41 h [day 1] to 0.91 h [day 80]). Similar results were obtained with saliva, and there were significant increases in the AUCs. The good correlation between the plasma and saliva data suggests that saliva sampling can be valid for acetaminophen pharmacokinetics. The changes in Cmax and tmax indicated more rapid drug absorption, which could have been as a result of faster gastric emptying or an increased blood flow to the intestine.

Influence of simulated weightlessness on the pharmacokinetics of acetaminophen administered by the oral route: a study in the rat

During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal‐models such as the Morey‐Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible ‘stress effect’ caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high‐performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow.

Influence of pre-analytical conditions on plasma ribavirin concentrations.

Ribavirin (CAS 66510-90-5) associated to peginterferon (CAS 99210-65-8) is the current standard treatment for chronic hepatitis C. Exposure to ribavirin influences the virological response and anemia. Therefore monitoring plasma concentration of ribavirin is a useful tool for individualizing ribavirin dosing regimens. Ribavirin is a substrate of several nucleoside transporters that play a role in its distribution in erythrocytes. After blood sampling, it is essential to limit this mechanism. The aim of this study was to evaluate the influence of temperature and time on ribavirin plasma concentrations. Two blood samples, collected in EDTA tubes, were taken at the same time from 23 patients. One sample was conserved on ice whereas the second one was kept at room temperature during transport to the laboratory. Upon receipt at the laboratory and at different times post-reception (from 1 to 3 h), 1.5 mL of blood from each sample was centrifuged to obtain plasma that was then stored at -20 degrees C until assay. Samples were maintained in the same conditions as during transport for the 3 h. Plasma ribavirin was analysed using an HPLC-UV system. The results showed that mean loss of ribavirin concentration, for samples kept on ice as well as at room temperature, was less than 3%, 9% and 13% after 1, 2 and 3 h, respectively. These results suggest that blood samples for ribavirin analysis can be sent at room temperature within a period of 2 h between sampling and centrifugation.

PharmacocinétiqueTuberculose : intérêt du dosage de l’isoniazide dans la prévention des effets hépatotoxiques

OBJECTIVE Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne. METHODS Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012. RESULTS The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients. CONCLUSION A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage.

Tuberculose : intérêt du dosage de l’isoniazide dans la prévention des effets hépatotoxiques

OBJECTIVE Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne. METHODS Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012. RESULTS The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients. CONCLUSION A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage.