Effect of Dose, Sex and Age on the Drug Disposition of Incadronate, a New Bisphosphonate, in Rat Bone

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Abstract
We investigated the effects of dose, sex and age on the uptake and elimination of incadronate, a new biosphos‐phonate, in rat bone after intravenous administration. Following administration of 0.03‐3 mg/kg to young male rats (age 7 weeks), intact drug concentration in humerus at 24 hr after administration (C24 hr) increased in a dose‐dependent manner, indicating the linear uptake of the drug into bone. The estimated bone uptake clearance of 0.13 ml/min./g bone is comparable to the estimated plasma flow rate in bone, suggesting that uptake into bone is plasma flow‐limited. Concentration from 24 hr after administration had declined bi‐exponentially. Although t1/2β(350‐444 days) was little altered among doses, t1/2αwas prolonged with increasing dose from 13.4 to 16.2 days. This effect seemed to be due to inhibition of bone resorption at higher doses resulting in the suppression of drug release from bone. No sex difference was seen on C24 hrin young rats, while the value in senescent (age 12 months) rats was 24% greater in females than in males. When comparing between ages it is seen that C24 hrvalues in senescent rats decreased to 50‐66% of those in young rats. As for elimination from bone, t1/2βvalues in senescent rats were shortened to 76‐79% of those in young rats. In contrast, little difference in t1/2αwas observed between ages or in either t1/2αand t1/2βbetween sexes.