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1. The metabolism of carteolol, a beta-adrenoceptor blocking drug, was investigated in male Sprague-Dawley rat liver microsomes. 2. The formation of 8-hydroxycarteolol was the principal metabolic pathway of carteolol in vitro and followed Michaelis-Menten kinetics with a K(m) = 11.0 +/- 5.4 microM and a Vmax = 1.58 +/- 0.64 nmol/min/nmol P450 respectively (mean +/- SD, n = 5). Eadie-Hofstee plot analysis of carteolol 8-hydroxylase activity confirmed single-enzyme Michaelis-Menten kinetics. 3. The cytochrome P450 isoforms involved in 8-hydroxylation of carteolol were investigated using selective chemical inhibitors and polyclonal anti-P450 antibodies. Quinine (Ki = 0.06 microM) and quinidine (Ki = 2.0 microM), selective inhibitors of CYP2D1, competitively inhibited 8-hydroxycarteolol formation. Furthermore, only anti-human CYP2D6 antibody inhibited this reaction. 4. These results suggest that carteolol is metabolized to 8-hydroxycarteolol by CYP2D1. The K(m) of carteolol for CYP2D1 in male rat liver microsomes was much greater than those of propranolol or bunitrolol, indicating that carteolol has a lower affinity for CYP2D1 compared with these other beta-adrenoceptor blocking drugs.

To elucidate the penetrability of carteolol, a beta-adrenoceptor antagonist (beta-blocker) into the brain of rats, intracerebral and serum concentrations of the compound were determined in male rats receiving single or repetitive oral administration of carteolol hydrochloride at 30 mg/kg. The time-course of the intracerebral concentration of carteolol following single IV administration of the compound at 10 and 30 mg/kg was also studied in male rats. A high-performance liquid chromatography method was used to determine the intracerebral and serum concentrations. Following single oral dosing, the intracerebral concentration of carteolol reached a maximum of 0.074 microgram/g at 2 h postdosing and declined with a half-life of 3.7 h, and the Cmax and AUC of carteolol in the brain were 12.5% and 19.8% of those in serum. The intracerebral and serum concentrations of carteolol were determined in male rats receiving repetitive oral dosing of the compound once daily for 7 days. The concentration of carteolol in the brain and serum at 1 h postdosing varied within a range of 0.059-0.091 microgram/g and 0.321-0.443 microgram/ml, respectively, throughout the dosing period, showing no changes in the penetrability of the compound into the brain due to repeated dosing. The concentration of carteolol in the brain and serum increased in a dose-dependent manner in rats receiving a single IV administration of the compound. The elimination half-life of carteolol in the serum and brain was 0.6-0.8 h and 1.3-1.7 h, respectively, in rats following single IV dosing of the compound. The half-life in the brain was about twice as long as that in the serum. The brain to serum concentration ratio was 0.306:0.499. From the above results, it was concluded that carteolol is distributed from the circulation to the brain with low penetrability.

Using an in vitro method the authors have investigated whether 8-hydroxycarteolol.HCl(8-OH carteolol) and 8-OH carteolol with benzalkonium chloride affected intact isolated porcine corneas to the same or to a different degree as carteolol.HCl (carteolol) or carteolol with benzalkonium chloride. These ophthalmically used drugs were applied as solutions of varying concentrations to the epithelial surface only, to the endothelial surface only, or to both surfaces of porcine corneas. The resultant opacities were determined using an opacitometer. In general, 8-OH carteolol and 8-OH carteolol with benzalkonium chloride caused less opacity to develop than carteolol and carteolol with benzalkonium chloride. This suggests that 8-OH carteolol may be a safer drug than carteolol for ophthalmic use. It is very interesting to note that compounds with two nitrogens, e.g., 8-OH carteolol, caused greater opacity in the intact cornea when applied to the endothelial surface than when applied to both the epithelial and endothelial surfaces; however, compounds with none or one nitrogen caused greater opacity in the intact cornea when applied to both surfaces than when applied to the endothelial surface.

We have tested the effects of carteolol and 8-hydroxycarteolol on cAMP generation in S49 lymphoma and BC3H1 smooth muscle-like cells. Carteolol was a high affinity beta-adrenoceptor antagonist in both systems but did not stimulate cAMP accumulation. The metabolite 8-hydroxycarteolol also was a high affinity antagonist. In contrast to its parent compound, however, it possessed an agonistic component which was considerably stronger than that of other beta-adrenoceptor blockers with intrinsic sympathomimetic activity, e.g. dichloroisoprenaline, pindolol, or celiprolol. These results suggest that metabolites can possess different pharmacodynamic properties in terms of beta-adrenoceptor interaction relative to parent compounds.

8-hydroxycarteolol hydrochloride (8-OH carteolol) is a main metabolite of carteolol hydrochloride (carteolol). We conducted a randomized double-masked single-drop study in an attempt to compare the effects of the ophthalmic solution of 8-OH carteolol and carteolol on intraocular pressure (IOP) in rabbits with water-load and monkeys. Both 8-OH carteolol (0.01 and 0.1%) and carteolol (1 and 2%) suppressed the water-load induced IOP rise in rabbits. 8-OH carteolol was more effective in suppressing the water-load induced IOP rise in rabbits compared with carteolol on equimolar basis. Both 8-OH carteolol (0.1%) and carteolol (2%) caused a statistically significant decrease in IOP in monkeys. 8-OH carteolol was estimated to be more potent than carteolol in lowering IOP on equimolar basis in monkeys.