Interspecies pharmacokinetic scaling of BSH in mice, rats, rabbits, and humans

Abstract

Sodium mercaptoundecahydrododecaborate or BSH is an important compound for boron neutron capture therapy (BNCT). The total clearance and steady state volume of distribution of BSH in humans and in laboratory animals were analyzed as a function of species body weight using the allometric equation for interspecies scaling. Significant linear relationships were obtained between log CLt (Lh-1) and log W (kg) (r = 0.972; p = 0.028) as well as log VSS (L) and log W (kg) (r = 0.999; p = 0.0005). The corresponding allometric equations were CLt = 0.127 W0.68 and VSS = 1.557 W0.87, respectively. BSH clearance in various species was shown to be a constant fraction (0.26) of creatinine clearance, the relationship being independent of body weight. Thus BSH clearance in various species occurred at similar pace when measured by a physiological parameter (creatinine clearance) rather than chronological time. Interspecies scale-up of plasma concentration-time data for the four species using a complex Dedrick plot resulted in similar profiles. Our results indicate that the BSH data obtained in laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.

Current data regarding the structure-toxicity relationship of boron-containing compounds

“…Furthermore, it is known that some BCCs tend to accumulate in the myocardium, bones, nails and hair (Mehta, 1995;Murray, 1998). Some studies suggest that kinetics is similar among mammals, but some researchers have found slight differences between rodents, particularly in renal depuration, and they suggest the importance of paying attention to these differences and therefore of being very careful in applying the conclusions from these studies to humans (Dourson, 1998;Pahl, 2005).…”

“…BCCs have also shown several advantages in regard to pharmacokinetics, including a high absorption rate, notable changes in the partition coefficient (compared to boron-free compounds with a similar structure, with the resulting effects on distribution), and the reduced feasibility of in vivo degradation (leading to the possible accumulation in specific tissues or organs) (Teshima, 1992;Mehta, 1995;Dourson, 1998;Murray, 1998;Koo, 2007;González, 2011;Tarres, 2014). Furthermore, it is known that some BCCs tend to accumulate in the myocardium, bones, nails and hair (Mehta, 1995;Murray, 1998).…”

Allometric principles for interspecies extrapolation in toxicological risk assessment—empirical investigations

“…Laznicek et al (1990) 2-Iodohippurate Intravenous CL tot Laznicek et al (1990) 3-Iodohippurate Intravenous CL tot Laznicek et al (1990) 4-Iodohippurate Intravenous CL tot Laznicek et al (1998) Lidocaine Intravenous V d , CL tot , t 1=2 Lin et al (1999) Monoclonal antibody against VEGF Intravenous V d , CL tot , C max , t 1=2 Lin et al (1999) Monoclonal antobody against VEGF Subcutaneous CL tot , C max , t 1=2 Mehta and Lu (1995) BSH Intravenous V d , CL tot Mitsuhashi et al (1990) ACNU Intravenous V d , CL tot Mordenti et al (1991) rCD4 Not stated V d , CL tot Mordenti et al (1991) CD4-IgG Not stated V d , CL tot Mordenti et al (1991) rhGH Not stated V d , CL tot Mordenti et al (1991) rt-PA Not stated V d , CL tot Mordenti et al (1991) Relaxin …”

A comparative study of allometric scaling with plasma concentrations predicted by species-invariant time methods

“…Kallynochrons and apolysichrons are transformed time units in elementary Dedrick plot and complex Dedrick plot, respectively. Though many investigators [12][13][14] have used the concept of species invariant time in their allometric analysis, a direct comparison of allometric approaches with species invariant time has not been systematically evaluated. Therefore, the objective of this study is to compare the predictability of allometric equations with that of species invariant time methods.…”