Dose size

Clearance is a critical parameter because of its role in determining a drug s dose size and frequency. First-pass clearance in combination with absorption determines a compound s bioavailability. Clearance and absorption in combination with potency determine dose size. Clearance and volume of distribution determine half-life, and thus dosing frequency. 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

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. 

The type and amount of carotenoids consumed affects carotenoid absorption. Absorption of (3-carotene from large doses is independent of dose size (Tanumihardjo 2002). The response of (3-carotene in serum and milk was similar in women supplemented with 60 or 210 mg of (3-carotene (Canfield and others 1997). In contrast, small carotenoid doses are more efficiently absorbed than large ones (West and Castenmiller 1998 Furusho and others 2000 Tanumihardjo 2002). 

Endothelial permeability Transporter proteins Enzymatic/metabolic activity Disease Tissue composition (drug sequestration) Dose size/volume Conformation Chemical stability Enzymatic stability... 

These values are obtained from in vitro enzyme experiments. From the previous relahonship between in vitro pharmacology measurements and free drug concentra-hons and those outHned here, it is reasonable to assume that cHnical dose size can be calculated from simple in vitro measurements. 

These concepts lead to two important observahons. Protein binding or hssue binding is not important in daily dose size. The daily dose size is determined by the required free (unbound) concentrahon of drug required for efficacy. Protein binding... 

Propranolol is considerably more potent (albeit less selective) than atenolol. Thus despite a much higher clearance than atenolol, both agents have a daily clinical dose size of around 25-100 mg. 

Amiodarone (Figure 8.2) is an efficacious drug that causes a number of side-effects. The presence of iodine in the molecule is unusual and hypo- and hyperthyroidism have been reported in patients. Although the loss of iodine is relatively slow the relatively large daily dose size and long half-life of the drug and its de-ethylated metabolite suggest that the presence of iodine in the molecule is responsible for its toxicity [3]. 

Table 8.2 gives a summary of the various toxicities and the stages at which they can occur. Also summarized are the causes for the specificity of the effect. With mutagenicity, certain pre-clinical toxicity, carcinogenicity and late clinical toxicology, the actual structure of the molecule is important and care should be taken to avoid the incorporation of toxicophores into compounds, as outlined about. Direct toxicity is addressed by ensuring the daily dose size is low, the intrinsic selectivity high and the physicochemical properties within reasonable boundaries. 

Pre-clinical and early clinical Toxicity directly related to dose size and intrinsic selectivity. Metabolites react with protein and cause cell death Overstimulation of receptor and others in superfamily. Metabolites not detoxified by glutathione etc. 

In contrast to these concentrations many clinically-used drugs, which are non-inducers are effective at doses up to two orders of magnitude lower. The need for high doses has other undesirable complications. As outlined above dose size is important in toxicity and enzyme inducers show a high level of adverse drug reactions affecting such organs and tissues as the liver, blood and skin (Table 8.4). 

This statement is somewhat at odds with the conventional view that idiosyncratic toxicology is dose-size independent. Idiosyncratic reactions are thought to result from an immune-mediated cell injury triggered by previous contact with the drug. The toxicity may appear after several asymptomatic administrations of the com-... 

Calculation of bioavailability requires a comparison of the AUcs following a non-intravenous and an intravenous dose, after correction for dose size. Without knowing the bioavaUabU-ity, only apparent clearance and volume of distribution can be calculated, and the ability to make predictions from these values is very limited. 

If you have done some clinical work you may have noticed that digoxin tablets come in two dose sizes - 0.25 mg (usually white), and 0.0625 mg (or 62.5 microgram - often blue in colour). One brand name is Lanoxin PG . Did you know that the PG stands for paediatric-geriatric which recognizes the immature kidneys of the infant and the failing kidneys of the elderly and the need to give smaller doses at both ends of life to avoid digoxin toxicity ... 

In further studies, the effect of intraperitoneal dose size upon the fate of cinnamyl anthranilate in mice was examined over a range of 5-250 mg/kg bw. No intact ester was found in the urine after 5 mg/kg bw, but at 50 mg/kg bw, 3.1 % of the dose was excreted as cinnamyl anthranilate and, at 250 mg/kg, the percentage was 2.2% (Keyhanfar Caldwell, 1996). 

The influence of dose size was also examined in male and female B6C3Fi mice given 0, 10, 100, 1000, 5000, 15 000 or 30 000 ppm (mg/kg diet) ciimamyl anthranilate in the diet for four days (Caldwell et al., 1985). The urinary excretion of cinnamyl anthranilate, hippuric acid and anthranilic acid within 24-h after removal of the test diet rose with increasing cinnamyl anthranilate dose. Cinnamyl anthranilate was detected in increasing quantities in the urine of male mice at 1000 ppm and above. In females, it was only seen at 5000 ppm and above and the levels were two- to nine-fold lower. 

There occur marked differences between rodent species and humans in the proportions of a dose excreted as these various major metabolites, and the dose size introduces further variables. Mr et al. (1989) gave male Sprague-Dawley rats, BALB/c mice and Syrian hamsters 0.1,0.7 and 7 mmol/kg bw dimethylformamide (approximately 7,50 and 500 mg/kg bw) by intraperitoneal injection and collected urine for 60 h (rat), 24 h (mice) and 36 h (hamster). In all cases, dimethylfonnamide and AMCC were very minor urinary metabolites, while the amounts of substances analysed as W-methylformamide ... 

Chidgey, M.A. J. Caldwell, J. (1986) Studies on benzyl acetate. 1. Effect of dose size and vehicle on the plasma pharmacokinetics and metabolism of fzzzei /zv/cz7c-> C]benzyl acetate in the rat. Food chem. Toxicol., 24, 1257-1265... 

One further point which should be considered is the importance of dose size. Because of the (R) — (S) conversion, the dosage of the (S) form administered may be as much as two or three times the anticipated dose. One can visualize an elderly 90 lb lady, with decreased renal function, who is administered a racemic drug. She receives the normal dose calculated for a 150 lb person (because of the way the tablets are made up). Because of decreased renal function and increased retention there is time for all the (i ) enantiomer to be converted to the (S) enantiomer. Effectively, she will receive three times the needed dose of the active drug and the area under the dose—time curve will be much greater. It is hardly surprising that adverse side effects sometimes occur.99... 

Thairs, S., et al. 1998. Effect of dose size, food and surface coating on the gastric residence and distribution of an ion exchange resin. Int J Pharm 176 47. 

Inclusion of the dose sizes in Equation 7.22 is necessary only if the two doses, D0route and /)0IV, are not equal. If all variables in Equation 7.21 are already known, AUC for an orally delivered drug can be quickly calculated with Equation 7.23. 

Larger, less frequent doses afford a broader range of Cp values. If Cp strays outside the therapeutic window, smaller, more frequent doses provide a narrower gap between the peaks and valleys of the Cp-time graph (Figure 7.17). The number of doses required to reach a pseudo Css range depends on kch kah, dose size, and dose frequency. 

FIGURE 7.17 Effect of dose size and frequency on Cp vs. time for an oral drug... 

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