Pharmacokinetics drug elimination

III. FIRST-ORDER PHARMACOKINETICS DRUG ELIMINATION FOLLOWING RAPID INTRAVENOUS INJECTION... 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

VI. PHARMACOKINETICS OF DRUG ELIMINATED BY SIMULTANEOUS METABOLISM AND EXCRETION... 

A second area of drug discovery and development in which enzyme reactions play a critical role is in the study of drug metabolism and pharmacokinetics. The elimination of xenobiotics, including drug molecules, from systemic circulation is driven by metabolic transformations that are entirely catalyzed by enzymes. Table 1.2 lists some of the enzyme-catalyzed transformations of xenobiotics that commonly contribute to drug molecule elimination. These biotransformation reactions... 

Hattis et al. (1987) examined the variability in key pharmacokinetic parameters (elimination half-lives (Ty ), area under the curve (AUC), and peak concentration (C ax) in blood) in healthy adults based on 101 data sets for 49 specific chemicals (mostly drugs). For the median chemical, a 10-fold difference in these parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, a 10-fold difference would correspond to only about 2.5 standard deviations in the population. The authors remarked that the parameters studied are only components of the overall susceptibility to toxic substances and did not include contributions from variability in exposure- and response-determining parameters. The study also implicitly excluded most human interindividual variability from age and diseases. When these other sources of variability are included, it is likely that a 10-fold difference will correspond to fewer standard deviations in the overall population and thus a greater number of people at risk of toxicity. 

Pharmacokinetics The elimination half-lives of these drugs range from 4 to 8 hours. Elimination is primarily via hepatic metabolism. Plasma concentrations of alosetron are 30% to 50% lower and less variable in men compared with women given the same dose. Plasma protein binding is 82% for alosetron, 65% for granisetron and 70% to 76% for ondansetron. The terminal elimination half-life of alosetron is approximately 1.5 hours. 

An important pharmacokinetic change that occurs in persons of advanced age is that of reduced renal drug elimination,... 

The pharmacokinetic term clearance (CT) best describes the efficiency of the elimination process. Clearance by an elimination organ (e.g., liver, kidney) is defined as the volume of blood, serum, or plasma that is totally cleared of drug per unit time. This term is additive the total body or systemic clearance of a drug is equal to the sum of the clearances by individual eliminating organs. Usually this is represented as the sum of renal and hepatic clearances CT = CT renal -I- CL hepatic. Clearance is constant and independent of serum concentration for drugs that are eliminated by first-order processes, and therefore may be considered proportionally constant between the rate of drug elimination and serum concentration. 

Prandota, J. (1985) Clinical pharmacokinetics of changes in drug elimination in children. Dev Pharmacol Ther 8 311-328. 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

Clearance (Cl) and volumes of distribution (VD) are fundamental concepts in pharmacokinetics. Clearance is defined as the volume of plasma or blood cleared of the drug per unit time, and has the dimensions of volume per unit time (e.g. mL-min-1 or L-h-1). An alternative, and theoretically more useful, definition is the rate of drug elimination per unit drug concentration, and equals the product of the elimination constant and the volume of the compartment. The clearance from the central compartment is thus VVklO. Since e0=l, at t=0 equation 1 reduces to C(0)=A+B+C, which is the initial concentration in VI. Hence, Vl=Dose/(A+B-i-C). The clearance between compartments in one direction must equal the clearance in the reverse direction, i.e. Vl.K12=V2-k21 and VVkl3=V3-k31. This enables us to calculate V2 and V3. 

These are factors governed by biological processes taking place in the animal itself. They will influence the levels of drug residues in animal tissues as well as the time course of drug elimination, which, in turn, depends on the pharmacokinetic profile of the drug. 

The 1996 Food Quality Protection Act (FQPA) now requires that an additional safety factor of 10 be used in the risk assessment of pesticides to ensure the safety of infants and children, unless the EPA can show that an adequate margin of safety is assured with out it (Scheuplein, 2000). The rational behind this additional safety factor is that infants and children have different dietary consumption patterns than adults and infants, and children are more susceptible to toxicants than adults. We do know from pharmacokinetics studies with various human pharmaceuticals that drug elimination is slower in infants up to 6 months of age than in adults, and therefore the potential exists for greater tissue concentrations and vulnerability for neonatal and postnatal effects. Based on these observations, the US EPA supports a default safety factor greater or less than 10, which may be used on the basis of reliable data. However, there are few scientific data from humans or animals that permit comparisons of sensitivities of children and adults, but there are some examples, such as lead, where children are the more sensitive population. It some cases qualitative differences in age-related susceptibility are small beyond 6 months of age, and quantitative differences in toxicity between children and adults can sometimes be less than a factor of 2 or 3. 

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