Abstract
We report the tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD [40-O-(2-hydroxyethyl)-rapamycin] and its metabolites in monkey lung transplant recipients as well as its interaction with cyclosporine as the Neoral formulation. After left unilateral lung transplantation, cynomolgus monkeys received by oral administration either 1) 1.5 mg/kg/day SDZ-RAD (n = 4); 2) 100 mg/kg/day cyclosporine (n = 4); 3) 0.3 mg/kg/day SDZ-RAD + 100 mg/kg/day cyclosporine (n = 6); 4) 1.5 mg/kg/day SDZ-RAD + 50 mg/kg/day cyclosporine (n = 5); or 5) SDZ-RAD and cyclosporine doses adjusted according to trough blood concentration measurements (n = 6). At the end of the observation period (usually 29 days after transplantation), and 24 h after the last doses, tissue samples were collected and analyzed with HPLC/mass spectrometry. Gall bladder, pancreas, the transplant lung, cerebellum, kidneys, and spleen had the highest SDZ-RAD concentrations. Coadministration of cyclosporine increased SDZ-RAD concentrations in most tissues as well as tissue-to-blood distribution coefficients. In contrast, SDZ-RAD had only a small effect on cyclosporine blood and tissue concentrations. Rejection in lung grafts in monkeys treated with either of the cyclosporine/SDZ-RAD combinations was significantly less than in the monotherapy groups (P < .002). Histological rejection scores were inversely correlated with SDZ-RAD concentrations in blood (r = −0.68;P < .001; n = 24), lymph nodes (P = −0.58; P < .003;n = 24), thymus (r = −0.63;P < .001; n = 23) and transplant lung tissue (r = −0.58;P < .003; n = 24). We conclude that, in addition to the synergistic pharmacodynamic interaction, a pharmacokinetic interaction resulting in higher SDZ-RAD tissue concentrations contributed to the significantly better immunosuppressive efficacy when both drugs were combined compared with monotherapy.
Footnotes
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Send reprint requests to: Uwe Christians, M.D., Ph.D., University of California-San Francisco, Department of Biopharmaceutical Sciences, School of Pharmacy, 533 Parnassus Ave., Room U66C, San Francisco, CA 94143-0446. E-mail:uwec{at}itsa.ucsf.edu
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↵1 This study was supported in part by the Alexander von Humboldt-Foundation, Grant V-3-FLF-1052812 (to N.S.); the Deutsche Forschungsgemeinschaft Grants Ch 95/6-2 (to U.C.) and Ha 1967/2-1 (to B.H.); National Institutes of Health Grants CA72006 and GM26691 (to L.Z.B.); the Ralph and Marian Falk Medical Research Fund; the Hedco Foundation; and a grant from Novartis Pharma AG, Basel, Switzerland (to R.E.M.).
- Abbreviations:
- FKBP
- FK-binding protein
- CYP
- cytochrome P450
- MS
- mass spectrometry
- amu
- atomic mass units
- Received November 1, 1999.
- Accepted March 27, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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