Physiological pharmacokinetics

A discussion of the bases of physiological pharmacokinetics is followed by a brief review of the fundamental mass balance equations of the models. Some examples are outlined, together with a listing of published reviews which give many more references and detailed examples. Finally, some thoughts on future research directions are presented.     

Kemantane pharmacokinetics in rats

Pharmacokinetics of novel immunostimulating drug kamantane was studied by using gas-liquid chromatography in experiments on rats. It was found that kemantane biotransformed rapidly after oral administration with the forming of active metabolite. Kemantane and its metabolites are distributed rapidly from the blood to organs. The drug is eliminated from the organism of rats as metabolite.     

Interspecies extrapolation of pharmacokinetics

The purpose of this paper is to use physiologically based pharmacokinetic models to demonstrate that if toxic response is a function of the time profile in physiological time of the concentration of the toxic moiety in the target tissue, then the appropriate interspecies scaling law for toxic compounds which are metabolically deactivated is mg kg-1 per unit of physiological time (mg kg-1 pt-1). At low dose rates this metric is approximately equivalent to mg kg-0.75 day-1. For reactive metabolites which are spontaneously deactivated, an approximate interspecies scaling law is mg kg-1 day-1.     

Gonadotropin-releasing hormone (GnRH) pharmacokinetics: peptide hormone pharmacokinetics needs clarification

The plasma level curves of the peptide hormone gonadotropin-releasing hormone (GnRH) after its intravenous, intramuscular, and intraperitoneal administration into rats were fitted according to a two- (i.v.) and one-compartment model (i.m., i.p.), respectively. From the pharmacokinetic parameters it is concluded that urinary excretion and proteolytic degradation by kidney and liver are not sufficient to fully account for the clearance of the hormone and that, therefore, proteolytic degradation by tissues may play a role for the elimination of GnRH. This may be generally true with other short peptide hormones. The GnRH pharmacokinetics is shown as an example to underline that there presently exist problems of interpreting pharmacokinetic data of peptide hormones and that there is a need for a close interplay between biochemical and pharmacokinetic studies on peptide hormones for their pharmacokinetic behaviour to be understood.     

Interferon: pharmacokinetics and toxicity

Interferons disappear rapidly from the serum of animals and man, and the kidney may be the major site of interferon destruction. The relevance of serum levels of interferons to their therapeutic activity has not been clearly established, particularly as the stimulation of host defence mechanisms by interferons may be important. Relatively low serum levels of antiviral activity are seen after intramuscular injections of fibroblast interferon compared with those after the same dose of leucocyte interferon. Injections of very pure leucocyte and lymphoblastoid interferons from several sources cause fever, headaches, malaise and myalgia associated with a corticosteroid response and probably with inflammatory prostaglandin synthesis. These reactions become less with repeated dosing but very large doses of lymphoblastoid interferon have been shown to cause liver damage and serious metabolic disturbances. Treatment with moderate doses of exogenous interferons may occasionally be associated with the development of neutralizing antibodies.     

4-Hydroxyanisole: human pharmacokinetics

The pharmacokinetic behaviour of 4-hydroxyanisole (4HA) has been studied in ten female patients with recurrent malignant melanoma confined to the lower limb. Ten grams of 4HA was infused twice each day via a catheter placed in the common femoral artery for a maximum of 4 days. Blood samples were collected after the first and fourth infusions in all patients and the serum 4HA concentration assayed. Following infusion, the serum 4HA concentration declined in two phases, the half-lives (t1/2) of the distribution and elimination phases being 6.3 and 70.9 min, respectively. The serum 4HA concentrations and area under the curve (AUC) declined significantly between the first and fourth infusions. There was a significant rise in the apparent volume of distribution (VD) of 4HA between these times but no change in the t1/2 of the elimination phase or the clearance rate. It is concluded that there is no evidence that enzyme induction influences the clearance of 4-hydroxyanisole from the bloodstream in the short-term. However, it may be appropriate to adjust dosage regimens to take account of the change in VD that occurs with time.     

Parameter optimisation in clinical pharmacokinetics

This paper describes a package of computer program designed to be used in Clinical Pharmacokinetics or Clinical Chemistry Laboratories to assist in the interpretation of plasma drug concentration measurements. A simple pharmacokinetic model is utilised, and values of the necessary parameters for the general population determined using standard nomograms. Parameter estimates for individual patients are obtained by a feedback process using Bayes' theorem and the principle of maximum likelihood. Thus optimal dosage regimes can be obtained for individual patients. The package can be used with a series of drugs.     

Effect of propranolol on lidocaine pharmacokinetics

The study aimed at investigating an effect of propranolol on lidocaine pharmacokinetic parameters, especially elimination rate and total clearance rate. The study was carried out in 8 rabbits with cross-over technique. The animals were examined twice. Sequence of therapy was established randomly. Some group of the animals were given propranolol and lidocaine first while the remaining animals were given lidocaine alone. Sequence of drugs administration was changed after one week. Propranolol was given in a single dose of 0.05 mg/kg b.w. intravenously. Lidocaine was injected in a single dose of 3 mg/kg b.w. during 5 minutes i.v. after a 30-minute interval. All drugs were injected into ear vein. Blood for assays was collected 8 times within 6 hours after lidocaine administration. TDx system manufactured by Abbott was used for drug concentration assay with immunofluorescence polarization method. One-compartment open model was used for calculations. The results were analysed with Student t-test for pairs. Significant decrease in AUC, marked decrease in distribution volume and total body clearance following lidocaine and propranolol were noted. The study has shown that there is interaction between propranolol and lidocaine leading to a decrease in total body lidocaine clearance.     

Indocyanine green pharmacokinetics in the rabbit

In a Latin square design, nine New Zealand white male rabbits (2.8-4.8 kg) each received intravenous indocyanine green (ICG) in doses of 2.5, 12.5, and 25 mg/kg. A period of 4 weeks separated consecutive experiments. A specific high-pressure liquid chromatographic (HPLC) assay and the traditional spectrophotometric (SPEC) method were used to monitor plasma ICG. The analyses demonstrated the ambiguous nature of the SPEC assay, and the HPLC procedure pointed to the presence of an unidentified ICG metabolite. Dose-dependent ICG disposition was evident from the ANOVA of the mean (+/- SD) clearances, namely, 17.09 (7.35), 4.50 (0.82), and 2.27 (0.57) mL X min-1 X kg-1 for the aforementioned doses, respectively. Analysis of variance of the clearances also demonstrated a significant ordering effect suggesting cumulative ICG toxicity. The mean ICG profiles for the three doses accorded with a novel three-compartment model containing two ICG distributional spaces in addition to a compartment (liver) responsible for ICG elimination from the circulation. A saturable uptake process into the eliminating compartment (Vmax = 0.93 mg X kg-1 X min-1; Km = 31.9 mg/L) accounted for the dose-dependent features. Additional studies in four unanesthetized rabbits with chronically catheterized bile ducts revealed no disparity between the SPEC and HPLC analyses of biliary ICG. The mean (+/- SD) ICG recovery in bile following an intravenous dose of about 12.5 mg/kg was 59.8 (16.3)%.     

A systems approach for tumor pharmacokinetics

Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.