Effect of posture on total phenytoin plasma concentration

Abstract

Standing for 35min increases venous haematocrit, haemoglobin and the plasma protein level by 10.3%, 10.8%, and 20.8%, respectively [1]. Standing for 90 min raises serum total calcium from 9.68mg.d1-1 to 10.02 mg. d1-1 [2]. Standing for 15 min increases plasma cholesterol by 10.4% and plasma triglycerides by 12.4% [3]. Standing for 30 to 40 min increases Vitamin B 12 and folate plasma levels by more than 10% [4]. The explanation for all these effects is that when a subject stands, fluid (up to 23% of plasma volume; [5]) leaves the circulation under hydrostatic pressure, particularly in the lower limbs [1, 6, 7], which swell [7]. This leads to an increase in the concentrations of such blood constituents as red cells, proteins and protein-bound substances (calcium, etc.), which do not readily pass through the capillary membrane. Reverting to the horizontal position reverses these changes. Phenytoin is highly bound to plasma proteins (69 to 96%; [8]), so it is highly likely that standing would increase the total plasma phenytoin concentration. To test this hypothesis, an experiment was conducted. The subjects were 7 epileptic inpatients treated with phenytoin and 4 healthy volunteers who took phenytoin for the experiment. There were 7 men and 4 women, mean (SD) age 49.2 (18.2) y (range 20-78 y); mean weight 61.7 (12.9) kg (range 39-83 kg). Informed consent was obtained. When the experiment started, the subjects were in the steady state and were taking a constant daily oral dose of phenytoin 100 to 300 mg (mean (SD) 231 (64.3) mg) given at 2 (08.00 h, 20.00 h), or at 3 (08.00 h, 12.00 h, and 18.00 h) in equal doses. Any concurrent medication remained constant during the two weeks preceding the experiment and during the two experimental days. The latter are called the "recumbent" and "erect" days. On the "recumbent" day, the subjects lay down from 00.00 h and remained recumbent until 08.45 h, blood being collected at 08.00 h and 08.45 h. They were given the last dose of phenytoin and any concurrent medication at least 12 h prior to blood sampling. They fasted for the 12 h preceding and during blood sampling. The drug, which would normally have been given at 08.00 h, was given once blood sampling was over. On the "erect" day, the procedure was the same, except that the subjects, who were recumbent until 08.00 and during the first 08.00 h blood sampling, stood up immediately after the 08.00 h blood sampling and remained standing as still as possible, with the arms dangling, until 08.45 h, when the second sample was collected, with the subject still erect. For five subjects the "recumbent" day preceeded the "erect" day by 24 h, and for 6 subjects the order was reversed (random allocation). Blood was collected as follows. Each morning on the two blood collection days, at 07.45 h an indwelling catheter was inserted into a superficial antecubital vein. It was removed once the last blood sample of the morning had been taken. Blood was collected from the catheter with a plastic syringe, after allowing blood to run freely

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