Obesity effects on nitrazepam disposition.

Abstract

1 Nitrazepam pharmacokinetics were studied in 14 obese (mean ± s.e. mean body weight 107 ± 9 kg; percent ideal body weight [IBW] .6 ng ml-1; NS) and time required after drug administration to reach peak concentration (1.52 ± 0.24-obese vs 1.59 ± 0.36 h; NS) indicated no differences between obese and control subjects.3 Elimination half-life was markedly increased in obese subjects (33.5 ± 2.2 vs 23.9 + 1.2 h; P < 0.001) due to increased apparent volume of distribution (Vd) (290 ± 45 vs 137 + 12 l; P < 0.005). Oral clearance was also increased in the obese subjects (101 ± 12.4 vs 66.8 ± 12.4 ml min-'; P < 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound-19.7 ± 0.4-obese vs 17.9 ± 0.3%; P < 0.005). 4 Correction of both Vd(2.62 ± 0.17-obese vs 2.22 ± 0.19 1kg-1; NS) and clearance (0.93 ± 0.06-obese ± 1.07 ± 0.07 ml min-' kg-1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight. Total Vd and percent IBW were highly correlated across subject groups (r = 0.87; P < 0.001) as were clearance and percent IBW (r = 0.77; P < 0.001). 5 Although clinical correlations are not established, unchanged absorption parameters between control and obese groups suggest no need for nitrazepam dose adjustment for obese insomniacs with difficulty falling asleep.

Anesthesia in the obese patient: Pharmacokinetic considerations

“…Abernethy and Greenblatt evaluated in several studies the effects of obesity on the disposition of different benzodiazepines, including diazepam, alprazolam, nitrazepam, lorazepam, and midazolam [18,[70][71][72][73]. All of these studies showed a significant increase in both volume of distribution and elimination half-life, with a significant correlation between lipid solubility and the extent of their distribution in the excess fat.…”

Effect of lipophilicity on drug distribution and elimination: Influence of obesity

“…All clinical protocols were reviewed and approved by the applicable institutional review boards, and all study participants provided written informed consent. Nineteen candidate drugs (Table 1) were administered in single-dose pharmacokinetic studies in healthy young volunteers of "normal weight" [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Excepting imipramine and propranolol, kinetic studies were also conducted in comparison cohorts of otherwise healthy obese subjects matched for age and gender (Table 2).…”

Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

“…Because transporters are responsible for a significant phase of chemical handling, this observed change in transporter expression implies that obese mice should have differential patterns of chemical absorption and elimination. Multiple drugs show altered pharmacokinetics and toxicokinetics in obese patients and the underlying reasons for altered pharmacokinetics in obese patients have not been well defined, but alterations in drug transporter expression could contribute to these observations (Bergman et al, 2007;Edelman et al, 2009). Abernethy et al (1986 reported altered disposition of nitrazepam in obese human subjects.…”