J.T. Doluisio

Pharmacokinetics of pentobarbital after intravenous and oral administration

The plasma levels in humans of pentobarbital were determined after intravenous administration of a 50 mg dose. It was found that pentobarbital is distributed in at least two kinetically distinct body compartments: a central, or “serum” compartment and a peripheral, or “tissue,” compartment. By use of established mathematical techniques, values were assigned to the rate constants controlling the distribution and overall elimination of the drug from the body. The oral absorption of pentobarbital in fasted and nonfasted subjects was determined by mathematical analysis of the plasma level data following oral administration of a 50 mg dose. It was found that the presence of food significantly reduces the apparent absorption rate constant but not the amount absorbed. The absorption of a second dose, given 1.5 hr after the first dose, in nonfasted subjects was not affected, and a rapid increase in plasma levels occurred after this administration.

Influence of repetitive dosing of tetracyclines on biologic half-life in serum.

The apparent biologic half‐lives of tetracycline, demethylchlortetracycline, methacycline, and doxycycline were found to increase from 6.3, 11, 7, and 8.3 hours to 10, 14.7, 11, and 14.5 hours, respectively, during 4 days of repetitive dosing (every 12 hours). Steady‐state serum levels predicted mathematically on the basis of the latter biologic half‐lives agreed with those observed experimentally, whereas steady‐state serum levels predicted on the basis of the biologic half‐life calculated from single‐dose studies did not. A method was developed for estimating the biologic half‐life from steady‐state serum level data; these estimates agreed well with the biologic half‐life estimated from semilogarithmic plots of serum level versus time data during the steady state and after dosing had ceased. Capsules of tetracycline phosphate complex, tablets of demethylchlortetracycline hydrochloride, capsules of methacycline hydrochloride, and capsules of doxycycline hyclate were found to produce comparable serum levels of antibiotic activity when administered at recommended doses every 12 hours.

Pharmacokinetics of kanamycin following intramuscular administration

The pharmacokinetics of intramuscularly administered kanamycin in normal healthy adults was found to be independent of dose. Plasma levels were adequately described by a one-compartment body model characterized by an elimination half-life of 2.4 hr and a volume of distribution of 19.6 liters. The renal clearance of kanamycin in normals was found to be about 4.6 liters/hr. The Cutler and Orme relationship, kanamycin half-life=3 × serum creatinine (mg %), was found to accurately estimate kanamycin half-lives in patients with varying degrees of renal insufficiency. In normal subjects, kanamycin serum levels during repetitive dosing were accurately predicted from single-dose studies.

Physiological factors affecting intestinal drug absorption.

Abstract An in situ technique for determining drug absorption rates from isolated segments of the gastrointestinal tracts of anesthetized animals has been described. In rats, the absorption half-lives for salicylic acid, barbital and haloperidol were found to be 8, 19 and 32 min respectively. When a fasting period exceeding 20–25 hr preceded the experiments, the absorption rates were found to decrease significantly and approximately in proportion to the fasting time. The influence of alterations in mesenteric blood flow on the absorption profile of sulfaethidole was investigated in anesthetized dogs. Reduction of intestinal blood flow to approximately 65%, 35% or 0% of initial values resulted in significant increases in absorption half-life. It is suggested that prolonged inanition may inhibit the intestinal drug absorption process by virtue of an induced diminution in intestinal blood perfusion.

The role of the kidney in the elimination of cephapirin in man

A pharmacokinetic model was developed to describe the absorption, distribution, metabolism, and excretion of cephapirin and its major metabolite, desacetylcephapirin, following intravenous and intramuscular administration of cephapirin in healthy adult subjects. The model involved a two-compartment open model for cephapirin in plasma and extravascular tissues and included metabolism of cephapirin to desacetylcephapirin in both the plasma compartment and the kidney. Renal metabolism of cephapirin was followed by excretion of the desacetylcephapirin into the urine. Clearance calculations and digital computer simulation supported these features of the model.