Circadian variation in the disease activity of rheumatoid arthritis has been established. Several nonsteroidal anti-inflammatory drugs have been studied for their chronokinetic behaviour. Time dependent influence of diazepam on the pharmacokinetics of diclofenac and naproxen has been reported. We report the time dependent influence of diazepam on the pharmacokinetics of ibuprofen in healthy subjects. Either ibuprofen or ibuprofen with diazepam was administered at 10.00 or 22.00 hours to eight healthy volunteers in a randomized crossover study. Serum ibuprofen levels were estimated by high performance liquid chromatography. There was a significant (p < 0.05) increase in mean elimination half life (2.39 +/- 0.42 to 3.59 +/- 0.35 h) following ibuprofen and diazepam administration compared to ibuprofen alone administered at 22.00 hours. The mean clearance of ibuprofen was therefore lowered from 62.7 +/- 8.9 to 41.7 +/- 2.6 ml/h/kg under the influence of diazepam during the night. Such a time dependent influence of diazepam on the pharmacokinetics of ibuprofen may be due to circadian variation in the pattern of protein production in the liver and/or competitive protein binding of the two drugs during the dark period.

The influence of time of administration on the serum levels of phenylpropanolamine when administered alone and in combination with chlorpheniramine maleate at two different times of a day was studied in healthy human volunteers in a randomized 4 x 4 Latin square crossover design with a washout period of ten days. Blood samples were collected at predetermined time intervals and serum samples were analysed for unchanged phenylpropanolamine using high performance liquid chromatography. The various pharmacokinetic parameters of phenylpropanolamine were calculated using model independent methods. There was a significant (P < 0.05) decrease in the rate of absorption of phenylpropanolamine following its administration in combination with chlorpheniramine maleate at 2200 hours. However, such a change was not observed for treatment at 1000 hours. The observed change may be due to the time dependent gastrointestinal effect of these drugs.