The effects of posture and sleep on pharmacokinetics

The effects of posture and sleep on the pharmaco-kinetics of five drugs (benzylpenicillin, gentamicin, sulphamethoxazole, trimethoprim and paracetamol) especially chosen for their disposition characteristics, were studied. To assess these effects, the drugs were administered, on separate occasions, to healthy young adults during ambulation, daytime bedrest and, with the exception of benzyl-penicillin, sleep. In addition, benzylpenicillin pharmacokinetics were determined following both intra-venous and intramuscular administration to the same subjects. New or improved high-performance liquid chromatography assays were developed for the determination of these drugs in biological fluids. Pharmacokinetic analysis of the drug concentration-time data was performed using traditional compartmental methods as well as a non-compartmental method using statistical moment theory. Generally, the results showed that posture had the greatest influence on the disposition of drugs with low renal extraction ratios and that sleep appears to have the same effects as bedrest on pharmacokinetics. With gentamicin, a highly polar compound with a low renal extraction ratio, ambulant subjects exhibited a larger volume of distribution and clearance than supine subjects. These findings may be due to posture-induced alterations in tissue perfusion and extracellular fluid distribution rather than to changes in renal function. These results may be clinically important; especially the finding that gentamicin C2 had a longer mean residence time than the other major components since it has been suggested, recently, that gentamicin C2 is the most nephrotoxic of the components. Sulphamethoxazole, a weak acid, was found to have a shorter half-life and greater urinary excretion rate during bedrest than during ambulation and a direct relationship was shown between the urinary excretion rate of the drug and both urinary pH and urine flow. Both these factors had higher values during bedrest. Trimethoprim, a weak base, is less sensitive to urine pH changes over the range observed and, consequently, the disposition of this drug was unaffected by posture or sleep. Unlike gentamicin and sulphamethoxazole, the pharmaco-kinetics of benzylpenicillin and paracetamol were unaffected by posture. Although the mean plasma benzylpenicillin levels were lower for bedrest than for ambulation, there were no significant differences between ambulation and bedrest for any of the derived pharmacokinetic parameters and thus it is suggested that the posture-dependent changes in the disposition of the penicillins reported by other workers may be related to the level of exercise undertaken in those studies. Paracetamol elimination was affected by neither change of posture nor sleep but the rate of absorption appeared to be slowest during sleep. These findings are in accordance with the low hepatic extraction ratio of paracetamol and the slower gastric emptying in supine and sleeping subjects. Overall, therefore, these studies show that change of posture can cause significant changes in the pharmaco-kinetics of certain drugs, especially polar compounds with low renal clearance and weak acids whose elimination is sensitive to changes in urine pH and urine flow. In conclusion, it is recommended that the posture of the patient should be taken into account in the design of pharmacokinetic studies and dosage regimes.