Partitioning of Morphine Derivatives and Metabolites

We would like to briefly present a summary of an extensive study of the partitioning behavior of morphine and a series of morphine derivatives, including 3- and 6-glucuronides (M3G and M6G). Details of the study will soon appear elsewhere (S. S. Davis et al., in preparation). Fig. 17 illustrates the lipophilicity curves of the family of compounds we examined. It is interesting to see how the ranking of lipophilicities varies with pH. At pH 7.4, the molecules have the following lipophilicity ranking, with D74 values in parentheses: buprenorphine (5600) » diacetylmorphine (7.1) >6-acetylmorphine (4.1) > codeine (1.7) > morphine (0.9) > morphine-6|3-D-glucuronide (0.2) > morphine-3|3-D-glucuronide (0.08) > norcodeine (0.06) > nor-morphine (0.03). We were able to characterize the partitioning of the zwitterionic form of M3G and M6G under a variety of conditions. It is interesting and unexpected that M3G has virtually identical lipophilicity in octanol, chloroform and PGDP. This may be the consequence of the acid and base properties of the M3G zwitterion molecule offsetting proton donor/acceptor properties of the three partition solvents. The lipophilicity curve clearly indicates enhanced partitioning when the background KC1 concentration was raised from 0.15 m to 0.5 m: the log P of the zwitterion increased from -1.06 to -0.88 with the increased salt. This is about the magnitude to effect expected if the zwitterion partitioned as an ion triplet, (K+M3GH±Cr)0cT- When the charge centers are close to each other, as in phenylalanine, the log P of the zwitterion does not appear to show dependence on ionic strength (cf. Fig. 16a). However, in the M3G zwitterion, the two charge centers are far apart; this may be the reason we see ionic

Morphine Family Lipophilicity

Figure 17. Morphine and derivatives profiles. Bup, buprenorphine; Dam, diacetylmorphine; 6 Am, 6-acetylmorphine; Cod, codeine; Mor, morphine; M3G, morphine-3ß-D-glucuronide; M6G, morphine-6ß-glucuronide; nCod, norcodeine; nMor, normor-phine.

Morphine Family Lipophilicity logD

Figure 17. Morphine and derivatives profiles. Bup, buprenorphine; Dam, diacetylmorphine; 6 Am, 6-acetylmorphine; Cod, codeine; Mor, morphine; M3G, morphine-3ß-D-glucuronide; M6G, morphine-6ß-glucuronide; nCod, norcodeine; nMor, normor-phine.

Drug—Liposome Lipophilicity Profiles

Ibuprofen

logD 2

Drug—Liposome Lipophilicity Profiles

Ibuprofen

logD 2

8 10

8 10

Figure 18. Drug-multilamellar liposome lipophilicity profiles. The dotted curves are octanol/ water profiles for the three drug Ibuprofen (curve 1), propranolol (curve 6), and hydroxyzine (curve 10). The solid curves are the calculated drug-liposome profiles: (2) ibuprofen-DOPC; (3) ibuprofen-eggPC; (4) ibuprofen-eggPC/0.3 cholesterol; (5) ibuprofen-eggPC/0.6 cholesterol; (7) propranolol-eggPC/0.3 cholesterol; (8) propranolol-eggPC; (9) propranolol-DOPC; (11) hydroxyzine-DOPC.

strength dependence. The high-pH region shows the most dramatic increase, presumably with the partitioning of (K+M3G")0ct-

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