In Vivo Disposition of Dermorphin Analog (DALDA) in Nonpregnant and Pregnant Sheep1
- Hazel H. Szeto1,
- James F. Clapp2,
- Dominic M. Desiderio3,4,
- Peter W. Schiller5,
- Olga O. Grigoriants3,
- Yi Soong1,
- Dunli Wu1,
- Niculina Olariu2,
- Jih-Lie Tseng3 and
- Robert Becklin3
- 1Department of Pharmacology, Cornell University Medical College, New York, New York (H.H.S., Y.S., D.W.); 2Department of Reproductive Biology and Obstetrics and Gynecology, Case Western Reserve University and MetroHealth Medical Center, Cleveland, Ohio (J.F.C., N.O.); 3The Charles B. Stout Neuroscience Mass Spectrometry Laboratory (D.M.D., O.O.G., J.L.T., R.B.) and Departments of 4Neurology and Biochemistry (D.M.D.), University of Tennessee, Memphis, Tennessee; and 5Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec, Canada (P.W.S.)
Abstract
Although synthetic opioid peptide analogs have been used extensively to study the functional roles of opioid receptors, little is known about their in vivo disposition. Our goal was to develop novel opioid drugs with limited transfer across the placenta. DALDA (Tyr-d-Arg-Phe-Lys-NH2) is a potent and highly selective mu agonist that is quite polar because of its 3+ charge at physiological pH. It can therefore be expected that the distribution of DALDA across the placenta would be highly restricted. In this study, we determined the pharmacokinetics and placental transfer of DALDA after systemic administration in sheep. DALDA was infused intravenously to four nonpregnant and four pregnant sheep at a dose of 0.6 mg/kg/hr for 4 hr. Steady state plasma levels of DALDA were 5436 ± 464 ng/ml in nonpregnant sheep and 5214 ± 661 ng/ml in pregnant sheep. A one-compartment open model provided an excellent fit for nonpregnant and pregnant plasma data. The apparent volume of distribution was estimated to be 45.6 ± 4.4 and 59.2 ± 7.9 ml/kg in nonpregnant and pregnant animals, respectively. There was no difference in the elimination half-life of DALDA in nonpregnant (1.4 ± 0.1 hr) and pregnant (1.7 ± 0.2 hr) animals, and clearance was also similar in nonpregnant (23.1 ± 1.7 ml/kg/hr) and pregnant (23.7 ± 1.3 ml/kg/hr) animals. These data suggest that the distribution of DALDA is restricted to plasma volume and that its disposition is not altered in pregnancy. DALDA was not detected in any of the fetal plasma samples (<50 ng/ml), indicating that fetal plasma concentration is <1% of maternal concentration. The highly restricted placental distribution of DALDA suggests that it may be a promising opioid drug for obstetrical use.
Footnotes
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Send reprint requests to: Hazel H. Szeto, M.D., Ph.D., Department of Pharmacology, Cornell University Medical College, 1300 York Avenue, New York, NY 10021. E-mail:hhszeto{at}mail.med.cornell.edu
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↵1 This work was supported in part by National Institute on Drug Abuse Multicenter Consortium Grant PO1-DA08924.
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↵2 N. Shimoyama, M. Shimoyama, C. E. Inturrisi and H. H. Szeto, unpublished observations.
- Abbreviations:
- DALDA
- Tyr-d-Arg-Phe-Lys-NH2
- dermorphin
- Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH2
- DAMGO
- Tyr-d-Ala-Gly-Phe(NMe)-Gly-ol
- DPDPE
- Tyr-d-Pen-Gly-Phe-d-Pen
- DAMME
- Tyr-d-Ala-Gly-Gly-Met(O)-ol
- Vd
- apparent volume of distribution
- t½
- elimination half-life
- CL
- clearance
- MRT
- mean residence time
- AUC
- area under the plasma concentration-time curve
- AUMC
- area under the first moment of the plasma concentration-time curve
- HPLC
- high-performance liquid chromatography
- MS
- mass spectrometry
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- Received May 27, 1997.
- Accepted September 9, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
