Chlordiazepoxide, distribution

In 7 healthy young women who had taken oral contraceptives for more than 6 months the protein binding of chlordiazepoxide was reduced and its volume of distribution increased (6). The clearance of chlordiazepoxide is also reportedly reduced by oral contraceptives (7). 

Age-related changes in drug distribution have been reported. The apparent volume of distribution is somewhat larger in newborns and infants than in adults. The estimated volume of distribution of sulfa-methoxypyridazine in newborns and infants is 0.47 and 0.36 L/kg, respectively, whereas the values are 0.20-0.26 L/kg in children, adults, and elderly subjects. The volume of distribution of chlordiazepoxide is substantially larger in the elderly (0.52 L/kg) than in the young (0.42 L/kg). The age-related difference in the volume of distribution may be due to a difference in plasma protein binding and/or in the relative size of body compartments. 

Reymond and Toome12 found the distribution coefficient of chlordiazepoxide between n-octanol and pH 7.2 buffer to have a value ofl71at room temperature where D = octanol/ buffer12. 

Chlordiazepoxide is about 94 to 97% bound to plasma proteins, and has a distribution volume of 0.3 to 0.4 L/kg in males and a somewhat larger volume in females. 

Figure 1-3. Serum concentration-time curve after administration of chlordiazepoxide as an intravenous bolus. The experimental data are plotted on a semilogarithmic scale as filled circles. This drug follows first-order kinetics and appears to occupy two compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (f gj) can be extracted graphically as shown by measuring the time between any two plasma concentration points that differ by twofold. (See Chapter 3 for additional details.) (Modified and reproduced, with permission, from Greenblatt DJ, Koch-Weser J. Drug therapy Clinical pharmacokinetics. N Engl J Med 1975 293 702.)...

Van der Kleijn E, Protein binding and lipophilic nature of ataractics of the meprobamate and diazepine group. Arch. Int. Pharmacodyn., 179, 225-250 (1969). NB No references or experimental details given cited in Van der Kleijn E, Kinetics of distribution and metabolism of diazepam and chlordiazepoxide in mice. Arch. Int. Pharmacodyn., 178, 193-215 (1969). 

Whole-body autoradiography of mice was employed as the technique to study the distribution of diazepam, chlordiazepoxide, and their metabolites. The former con und was more highly localized in body fat thetn the latter however, the rate of penetration of chlordiazepoxide into the brain was slower than that of diazepam. The major metabolite of diazepam was the N-demethylated compound. vitro, in preparations of rat or mouse liver microsomes, the major metabolites of diazepam were N-methyloxazepam or N-demethyldiazepam, respectively. Diazepam inhibited the conversion by mouse liver microsomes of N-methyloxazepam to oxazepam. Prazepam, the cyclopropyl derivative of the N-methyl group of diazepam, was metabolized by the dog in a manner similar to that for dicusepam the major urinairy metabolite was oxazepam glucuronide. ... 

What is the volume of distribution of a foreign chemical Estimate the volume of distribution of chlordiazepoxide from Figure 6.8. 

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