Pharmacokinetics elimination rate/route

To facilitate the understanding of the pharmacokinetic concepts, the examples given previously are for the simplest and the most effective route of administration, that is, intravenous administration. When exposure is to toxic compounds (e.g., occupational or environmental exposure), however, other routes are frequently involved. These routes include respiratory, cutaneous, mucous, or oral uptake. In such cases, pharmacokinetic analyses are more complex since they should take into account the various processes responsible for the uptake of a xenobiotic. Usually, this consists of introducing into equations an additional term that contains a rate constant describing the uptake, operating in a direction opposite to, yet not conceptually different from the elimination rate constant. 

The advantages of using non-compartmental methods for calculating pharmacokinetic parameters, such as systemic clearance (CZg), volume of distribution (Vd(area))/ systemic availability (F) and mean residence time (MRT), are that they can be applied to any route of administration and do not entail the selection of a compartmental pharmacokinetic model. The important assumption made, however, is that the absorption and disposition processes for the drug being studied obey first-order (linear) pharmacokinetic behaviour. The first-order elimination rate constant (and half-life) of the drug can be calculated by regression analysis of the terminal four to six measured plasma... 

Pharmacokinetic parameters, such as elimination half life (ti/2), the elimination rate constant (K), the apparent volume of distribution (V) and the systemic clearance (Cl) of most drugs are not expected to change when different doses are administered and/or when the drug is administered via different routes as a single or multiple doses. The kinetics of these drugs is described as linear, or dose-independent, pharmacokinetics and is characterized by the first-order process. The term linear simply means that plasma concentration at a given time at steady state and the area under the plasma concentration versus time curve (AUC) will both be directly proportional to the dose administered, as illustrated in Fig. 15.1. 

Three studies report alterations in the pharmacokinetics of chloramphenicol hy paracetamol. The first was conducted in 6 adults in intensive care after an ohservafion thaf fhe half-life of chloramphenicol was prolonged hy paracefamol in children wifh kwashiorkor. The addition of 100 mg of intravenous paracetamol inereased the half-life of chloramphenicol in the adults from 3.25 to 15 hours. Ttowever, this study has been criticised because of potential errors in the method used to calculate the half-life, the unusual doses and routes of administration used, and because the pharmacokinetics of the chloramphenicol with and without paracetamol were calculated at different times after the administration of chloramphenicol. ft has also been pointed out that malnutrition (e.g. kwashiorkor) can increase the elimination rate and AUC of chloramphenicol independently of paraeetamol. ... 

In the development of most new active substances, it is required to investigate the disposition of the compound and its metabolite(s) and their rates and routes of elimination. This is generally carried out with radiolabelled compound, usually In the United Kingdom, approval of the Administration of Radioactive Substances Advisory Committee (ARSAC) is required for administration of radiolabelled compound to man. The purpose of the submission is to demonstrate that the dose of absorbed radiation is minimised by administration of the lowest dose that is consistent with meeting the objectives of the study. In general, the estimated absorbed radiation dose should be less than 500 xSv, but higher amoimts are permissible if they can be justified. The estimate is based on tissue distribution of radioactivity in animals and the pharmacokinetics in animals and man. 

Pharmacokinetics Venlafaxine is well absorbed (at least 92%) and extensively metabolized in the liver. ODV is the only major active metabolite. Renal elimination of venlafaxine and its metabolites is the primary route of excretion. Venlafaxine ER provides a slower rate of absorption but the same extent of absorption compared with the immediate-release tablet. 

Mecfianism of Action An ergotamine derivative, alpha-adrenergic blocker that directly stimulates vascular smooth muscle. May also have antagonist effects on sero-fonin. Therapeutic Effect Peripheral and cerebral vasoconstriction. Pharmacokinetics Slow, incomplete absorption from the gastrointestinal (GI) tract rate of absorption of intranasal route varies. Protein binding greaterthan 90%. Undergoes extensive first-pass metabolism in liver. Metabolized to active metabolite. Eliminated in feces via biliary system. Half-life 7-9 hr. 

Pharmacokinetic studies in mice, rats, and dogs showed that cephapirin was readily metabolized into desacetylcephapirin. The rate and the extent of this metabolism showed a decreasing tendency from rodents to dogs. In these species, the plasma elimination half-lives of cephapirin and desacetylcephapirin were 0.4-0.9 h. In dairy cows, cephapirin was mainly eliminated by the urinary route and, to a smaller extent, by the biliary route. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Solubility (see Section 3.3), for example, is an important factor in the absorption, distribution and elimination of a drug. Furthermore, the rate of drug dissolution, that is, the rate at which a solid drug dissolves in the aqueous medium, controls its activity when a solid drug is administered by enteral routes (see Section 2.6) as a solid or suspension. 

Biodistribution of liposomes is a very important parameter from the clinical point of view. Liposomes can alter both the tissue distribution and the rate of clearance of the drug by making the drug take on the pharmacokinetic characteristics of the carrier (10, 11). The pharmacokinetic variables of the liposomes depend on the physiochemical characteristics of the liposomes, such as size, surface charge, membrane lipid packing, steric stabilization, dose, and route of administration. As with other microparticulate delivery systems, conventional liposomes are vulnerable to elimination from systemic circulation by the cells of the reticuloendothelial system (RES) (12). The primary sites of accumulation of conventional liposomes are the tumor, liver, and spleen compared with non-liposomal formulations (13). Many studies have shown that within the first 15-30 min after intravenous administration of liposomes between 50 and 80% of the dose is adsorbed by the cells of the RES, primarily by the Kupffer cells of the liver (14-16). 

Elimination - Elimination is defined here as excretion and/or metabolism of intact drug from plasma. In general, the main excretion routes are renal and biliary, and the predominant metabolic route is hepatic. The pharmacokinetic parameters most widely used to characterize plasma concentration decay are the apparent first-order rate constant (K), elimination half-life (t] /2) > clearance (Cl). Clearance is defined as the... 

Figure 31.2 shows a more detailed scheme of the main routes of drug absorption, distribution and elimination. Pharmacokinetics is the study of the drug concentrations in the different parts of the organism as a function of time. These concentrations depend on the dose administered and upon the rate and extent of absorption, distribution and elimination. 

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