Three albuterol (salbutamol) new triesters (acetyl, isobutyryl and pivalyl) were prepared and evaluated in vitro (rate of chemical hydrolysis at different pH values, relative lipophilicity) and in vivo (depression of intraocular pressure, IOP, in a rabbit model of ocular hypertension). The three esters underwent quantitative hydrolysis in vitro to give the parent compound: first-order kinetics were observed, for several half-lives, for the disappearance of the compounds from solution at different pH values. The degradation mechanism, presumably involving a sequence of hydrolytic steps, was not investigated in detail. The rate constants for disappearance of the triesters and for formation of albuterol were in the order acetyl > isobutyryl > pivalyl; the relative lipophilicities of the compounds, as estimated by the corresponding reversed phase HPLC 'capacity factors', were in the order albuterol < acetyl < isobutyryl < pivalyl. When tested for reduction of IOP, all three ester solutions proved significantly more active than albuterol at several times after administration. The tripivalyl ester, in particular, after 5 h appeared more active than the other two esters, and, together with the triisobutyryl ester, was significantly more active than the triacetate after 8 h. These findings confirm the.important influence of (pro)drug lipophilicity on transcorneal penetration. The in vivo tests also indicated that the ocular irritant properties of the parent drug were still present, albeit to a smaller degree, in the triester derivatives.
Albuterol prodrugs for ocular administration: Synthesis and evaluation of the physico-chemical and IOP-depressant properties of three albuterol triesters
CHETONI, PATRIZIA;CROTTI, PAOLO;
1994-01-01
Abstract
Three albuterol (salbutamol) new triesters (acetyl, isobutyryl and pivalyl) were prepared and evaluated in vitro (rate of chemical hydrolysis at different pH values, relative lipophilicity) and in vivo (depression of intraocular pressure, IOP, in a rabbit model of ocular hypertension). The three esters underwent quantitative hydrolysis in vitro to give the parent compound: first-order kinetics were observed, for several half-lives, for the disappearance of the compounds from solution at different pH values. The degradation mechanism, presumably involving a sequence of hydrolytic steps, was not investigated in detail. The rate constants for disappearance of the triesters and for formation of albuterol were in the order acetyl > isobutyryl > pivalyl; the relative lipophilicities of the compounds, as estimated by the corresponding reversed phase HPLC 'capacity factors', were in the order albuterol < acetyl < isobutyryl < pivalyl. When tested for reduction of IOP, all three ester solutions proved significantly more active than albuterol at several times after administration. The tripivalyl ester, in particular, after 5 h appeared more active than the other two esters, and, together with the triisobutyryl ester, was significantly more active than the triacetate after 8 h. These findings confirm the.important influence of (pro)drug lipophilicity on transcorneal penetration. The in vivo tests also indicated that the ocular irritant properties of the parent drug were still present, albeit to a smaller degree, in the triester derivatives.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
