Changes In Drug Disposition Research Articles

Changes in drug disposition

Changes in drug disposition

The effects of cigarette smoking on plasma concentrations of gastric antisecretory drugs.

Plasma concentrations of cimetidine and ranitidine were measured after oral administration (n = 5 for cimetidine, n = 5 for ranitidine) or intravenous administration (n = 6 for cimetidine, n = 4 for ranitidine) in habitual smokers, once when cigarettes were smoked and again on a separate day when cigarettes were prohibited. After oral administration plasma concentrations of both drugs rose more rapidly and peak plasma concentrations were achieved earlier when cigarettes were smoked. However, plasma concentrations of the drugs subsequent to the peak were significantly lower when cigarettes were smoked. Cigarette smoking had no effect on plasma blood concentrations of either drug when administered intravenously. In eight healthy smokers cigarette smoking increased the gastric emptying of a liquid test meal by 28% compared with non-smoking control rates. In habitual smokers cigarette smoking alters the blood concentrations of antisecretory drugs in a manner which appears attributable to an increase in the rate of gastric emptying. The observed changes in drug disposition may contribute to the loss of gastric secretory inhibition observed in duodenal ulcer patients who are smokers.

Drugs and nutrition in old age

Drug effects are influenced by physiologic and pathologic changes that occur as a consequence of aging. The elderly may be more disposed to drug-induced nutrient depletion because of chronic illness, inadequate diet and long-term drug use. Digoxin, isoniazid, corticosteroids, diuretics and psychoactive agents pose special hazards to the nutritional status of elderly patients. On the other hand, dietary factors, such as protein levels or vitamin deficiencies, may be important determinants of age-related changes in drug disposition or toxicity.

A SHEEP PREPARATION FOR STUDYING INTERACTIONS BETWEEN BLOOD FLOW AND DRUG DISPOSITION. I: PHYSIOLOGICAL PROFILE

A sheep preparation has been developed which allows repeated measurements of regional blood flow, oxygen consumption and drug disposition in awake, unrestrained animals. This allows systematic studies of both acute changes, such as haemodynamic disturbances, and of chronic changes, such as enzyme induction, to be carried out. Good agreement was shown between the values for cardiac output and regional blood flow obtained by the Fick and indicator dilution methods, and those obtained by others using microspheres. Significant day-to-day fluctuations in haemodynamic indices were shown to occur; assumptions that hepatic or renal blood flows are constant fractions of cardiac output, or that renal or hepatic flow indicator extraction ratios remain unchanged from day-to-day, will lead to significant errors. Thus, control measurements for each experiment are necessary. It is proposed that physiological models for studying drug disposition based on data from awake, unrestrained animals may provide insight into some mechanisms of changes in drug disposition that cannot be obtained using the traditional compartmental method.

Drug toxicity and hormonal dysfunction.

Abnormal levels of hormones can exert profound changes in drug disposition and the number and affinity of receptors. In endocrine diseases a variety of organ functions change. These disease related changes in the function of organs involved with the distribution, metabolism and excretion of drugs can profoundly alter drug disposition. If not taken into account when devising dosage regimens drug toxicity can result.

Altered jejunal surface pH in coeliac disease: its effect on propranolol and folic acid absorption.

1. Propranolol and folic acid absorption were studied separately in healthy subjects, non-coeliac patients and patients with treated and untreated coeliac disease. 2. The surface pH of jejunal biopsy samples was measured with a pH electrode. 3. When compared with values found in healthy subjects, plasma propranolol levels were elevated in coeliac disease and, in contrast, serum folic acid levels were depressed after oral administration of the drug. Jejunal surface pH was more alkaline in the coeliac groups than in the healthy and non-coeliac subjects. 4. Pharmacokinetic analysis of the plasma drug levels allowed evaluation of the rate constants associated with absorption and elimination. The absorption rate constant was decreased for folic acid in the coeliac group, but increased for propranolol. These changes correlated with variation in surface pH. 5. Although the changes in drug disposition in treated and untreated coeliac disease are the result of several factors, it is suggested that jejunal surface pH may affect the rate of absorption and therefore the plasma concentration-time profile of drugs which undergo dissociation.

Pharmacokinetics of Tetracycline in Nutritional Oedema

Tetracycline pharmacokinetics were studied in a group of normal subjects and in patients with nutritional oedema. Though both groups of subjects received similar dose per kilogram body weight, plasma concentrations and area under the curve (AUC) were significantly higher in nutritional oedema patients. The total body clearance of the drug was reduced due to significant reductions in renal and non-renal clearance of drug. The volume of distribution (VB) was low, with significant increase in rate of transfer of drug from peripheral to central compartment (K21), indicating poor tissue sequestration of the drug in nutritional-oedema patients. In some respects, these alterations in kinetics of tetracycline in nutritional-oedema patients are different from our earlier observations made in undernourished subjects who had mild and moderate forms of malnutrition. These results suggest that changes in disposition of drugs are also influenced by the severity of malnutrition, and demand suitable alterations in dosage regimen.

The effect of probenecid on the pharmacokinetics and distribution of cefoxitin in healthy volunteers.

1 Cefoxitin was given by acute intravenous injection to six healthy volunteers, in a crossover study to investigate the effects of concurrent probenecid administration. 2 Serum antibiotic concentrations were determined by microbiological assay. Cefoxitin concentrations were simultaneously determined in the fluid of blisters produced by topical cantharides. All antibiotic was accounted for in the urine. 3 Cefoxitin was administered by intravenous infusion, subsequent to a loading dose, to produce steady state levels in the region of 10 microgram/ml, in one volunteer. The procedure was later repeated after prior administration of probenecid in the same subject. 4 Pharmacokinetic analyses indicated significant changes only in the parameters associated with renal excretion of drugs. Clearance was reduced by half. 5 The absolute and relative amounts of antibiotic in the central and peripheral compartments were calculated for both modes of administration. In the acute study probenecid produced a small change in distribution away from the peripheral or tissue compartment, towards the central compartment. 6 There was no elevation of initial serum concentrations and sustained levels of antibiotic could be accounted for principally by retarded excretion produced by probenecid, with little contribution by alteration in the disposition of antibiotic. 7 The sustained serum levels of cefoxitin that resulted from its decreased excretion were also reflected in blister fluid. It was concluded that the sustained cefoxitin levels produced by probenecid resulted in similar raised levels in the peripheral or "tissue' compartment, since the redistribution away from the peripheral compartment did not contribute materially to other changes in disposition of drug.

Desmethyldiazepam kinetics in the elderly after oral prazepam.

Our subjects were 15 young (aged 22 to 42 yr) and 14 elderly (aged 62 to 85 yr) people who took single oral doses of 20 mg prazepam. Plasma desmethyldiazepam (DMDZ) concentrations were determined in venous blood samples drawn up to 9 days after the dose. Appearance in blood of DMDZ was slow, with peak plasma levels reached in an average of 10 to 20 hr. First-order DMDZ appearance was observed in only 17 subjects. Volume of distribution of total DMDZ (range, 1.33 to 6.30 l/kg) and of unbound DMDZ after correction for protein binding (range, 43 to 243 l/kg) was larger in women than in men of all ages, and in the elderly as opposed to the young. Elimination half-life (range, 29 to 224 hr) rose with age in men (r = 0.66, p < 0.01) but not in women (r = -0.02). Clearance of unbound DMDZ (range, 2.9 to 31.2 ml/min/kg) was greater in women than in men of all ages, and declined with age in men (r = -0.40) but not in women (r = -0.06). As in the case of diazepam, age can influence DMDZ kinetics, but changes in drug disposition with age may differ between sexes.

Paracetamol pharmacokinetics in thyroid disease.

The absorption, distribution and elimination of oral paracetamol have been studied in patients before and after treatment of thyrotoxicosis (n = 7) and hypothyroidism (n = 4). Absorption was faster in patients with untreated thyrotoxicosis than when subsequently euthyroid. The peak paracetamol concentration, however, was lower in thyrotoxic patients due to an apparent increase in the total body clearance and a shorter plasma half-life. Both absorption and elimination rates were reduced in hypothyroid patients, but were not significantly different from the euthyroid results. When estimated using a two compartment model the total volume of distribution and the hybrid distribution rate constants were unrelated to thyroid status, but the apparent volume of the central compartment was significantly greater in the thyrotoxic group. These changes in drug disposition may contribute to differences in drug response seen in thyroid disease.

Indobufen (K 3920), a new inhibitor of platelet aggregation: Effect of food on bioavailability, pharmacokinetic and pharmacodynamic study during repeated oral administration to man

The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.