Intravenous drug administration pharmacokinetics

Dominic JA, Bourne DW, Tan TG, Kirsten EB, McAllister RG Jr. The pharmacology of verapamil. IB. Pharmacokinetics in normal subjects after intravenous drug administration. J Cardiovasc Pharmacol 1981 3(l) 25-38. 

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

Various characteristics of the molecule influence its chances of reaching its target receptor since they influence the nature and extent of the body s effect on it. A drug s pharmacokinetic profile therefore determines the extent of the drug s opportunity to exert its pharmacodynamic effect. While there are various routes for human drug administration (oral rectal intravenous, subcutaneous, intramuscular, and intra-arterial injections topical and direct inhalation into the lungs), the most common for small-molecule drugs is oral administration, and discussions in the first part of this chapter therefore focus on oral administration. (In contrast, biopharmaceuticals are typically administered by injection, often directly into the bloodstream.)... 

If the time elapsed since drug administration (t) is known, together with some pharmacokinetic data for the drug, then it should be possible to estimate the original dose (D) of the drug. Thus, for a drug given by intravenous injection,... 

FIGURE 10.1 Fit obtained using a one-compartment model (see Equation 10.6) to fit plasma concentration-vs-time data observed following intravenous bolus administration of a drug designates the actual measured concentrations and Cp-g represents the concentrations predicted by the pharmacokinetic model. (Adapted from Grasela XH Jr, Sheiner LB. J Pliarmacokinet Biopharm 1991 19(suppl) 25S-36S.)... 

There was a long period of time when it was not exactly clear how much and how long the reactivators of cholinesterase could be applied. The investigation about toxicity and pharmacokinetics of this compound clarifies this problem. From the results obtained [12] can be concluded that HI-6 when administrated intravenously or intramuscularly is rapidly eliminated by cats. Parenteral drug administration will need to be repeated every 3-4 h. to maintain effective plasma concentrations (about 4 pg/ml). 

Intravenous Drug Disposition. The estimation of primary pharmacokinetic parameters using noncompartmental analysis is based on statistical moment theory [45, 46]. The relationships dehned by this theory are valid under the assumption that the system is linear and time-invariant. For simplicity, we further assume that drug is irreversibly removed only from a single accessible pool (e.g., plasma space). Regardless of the route of administration, the temporal profile of plasma drug concentrations, Cp(t), can represent a statistical distribution curve. As such, the zeroth and first statistical moments (Mo and Mi) are defined as ... 

How the fundamental pharmacokinetic parameters of a drug are obtained following the intravenous bolus administration of a drug will be discussed below. These parameters, in turn, form a basis for making rational decisions about the dosing of drugs in therapeutics. The following assumptions are made in these discussions (Fig. 3.1) ... 

Gupta PK, Ehrnebo M. 1979. Pharmacokinetics of alpha isomer and beta isomers of racemic endosulfan following intravenous administration in rabbits. Drug Metab Dispos 7 7-10. 

McMahon B.M., Mays D., Lipsky J., Stewart J.A., Fauq A., Richelson E. Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. Antisense Nucleic Acid Drug Dev. 2002 12 65-70... 

Eichelbaum, M., Ochs, H. R., Roberts, G., Somogyi, A., Pharmacokinetics and metabolism of antipyrine (phenazone) after intravenous and oral administration, Drug Res. 1982, 32, 575-578. 

Thus, %F is defined as the area under the curve normalized for administered dose. Blood drug concentration is affected by the dynamics of dissolution, solubility, absorption, metabolism, distribution, and elimination. In addition to %F, other pharmacokinetic parameters are derived from the drug concentration versus time plots. These include the terms to describe the compound s absorption, distribution, metabolism and excretion, but they are dependent to some degree on the route of administration of the drug. For instance, if the drug is administered by the intravenous route it will undergo rapid distribution into the tissues, including those tissues that are responsible for its elimination. 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

Yoshimura et al. [132] studied the pharmacokinetics of primaquine in calves of 180—300 kg live weight. The drug was injected at 0.29 mg/kg (0.51 mg/kg as primaquine diphosphate) intravenously or subcutaneously and the plasma concentrations of primaquine and its metabolite carboxyprimaquine were determined by high performance liquid chromatography. The extrapolated concentration of primaquine at zero time after the intravenous administration was 0.5 0.48 pg/mL which decreased with an elimination half-life of 0.16 0.07 h. Primaquine was rapidly converted to carboxyprimaquine after either route of administration. The peak concentration of carboxyprimaquine was 0.5 0.08 pg/mL at 1.67 0.15 h after intravenous administration. The corresponding value was 0.47 0.07 pg/mL at 5.05 1.2 h after subcutaneous administration. The elimination half-lives of carboxyprimaquine after intravenous and subcutaneous administration were 15.06 0.99 h and 12.26 3.6 h, respectively. 

---