title: Pharmacokinetics and pharmacodynamics analysis of transdermal iontophoresis of 5-OH-DPAT in rats: in vitro-in vivo correlation.
abstract: Pharmacokinetics and dopaminergic effect of dopamine agonist 5-OH-DPAT in vivo were determined following transdermal iontophoresis in rats based on drug concentration in plasma (C(p)) and dopamine levels in striatum (C(DA)). Correlation of the in vitro transport with the pharmacokinetic-pharmacodynamic (PK-PD) profiles was characterized in the transport in dermatomed rat skin (DRS) and rat stratum corneum (RSC). The integrated in vivo PK-PD and in vitro transport models successfully described time course of C(p), C(DA), and in vitro flux in DRS and RSC. Population value of steady-state flux (J(ss)) in vivo (31 nmol/cm(2) . h with 95% confidence interval (CI) = 20-41) is closer to J(ss) in vitro in DRS (61 nmol/cm(2) . h, CI = 54-67) than in vitro J(ss) in RSC (98 nmol/cm(2) . h, CI = 79-117). On the other hand, skin release rate constant (K(R)) in vivo was similar to the K(R) in RSC (4.8/h, CI = 2.4-7.1 vs. 2.6/h, CI = 2.5-2.6). Kinetic lag time (t(L)) in vivo was negligible, which is close to in vitro t(L) in RSC (0.0 h, CI = 0.0-0.1). Based on nonlinear mixed-effect modeling, profiles of C(p) and C(DA) were successfully predicted using in vitro values of J(ss) in DRS with K(R) and t(L) in RSC. A considerable dopaminergic effect was achieved, indicating the feasibility to reach therapeutically effective concentrations of 5-OH-DPAT upon transdermal iontophoresis.
authors.affiliation: Division of Drug Delivery Technology Leiden/Amsterdam Center for Drug Research, Einsteinweg 55 2300 RA Leiden, The Netherlands.
authors.forename: Akhmad Kharis
authors.initials: AK
authors.lastname: Nugroho
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Romeijn
authors.forename: Raphaël
authors.initials: R
authors.lastname: Zwier
authors.forename: Jan B
authors.initials: JB
authors.lastname: de Vries
authors.forename: Durk
authors.initials: D
authors.lastname: Dijkstra
authors.forename: Håkan
authors.initials: H
authors.lastname: Wikström
authors.forename: Oscar
authors.initials: O
authors.lastname: Della-Pasqua
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Joke A
authors.initials: JA
authors.lastname: Bouwstra
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000279:Administration, Cutaneous; D000818:Animals; D004298:Dopamine / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007478:Iontophoresis; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012867:Skin / Q000378:metabolism*
chemical_list: D018491:Dopamine Agonists; C011799:5-hydroxy-2-N,N-dipropylaminotetralin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D004298:Dopamine