Pharmacokinetics and pharmacodynamics of an investigational antipsychotic agent, CI-1007, in rats and monkeys.
OBJECTIVE
To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys.


METHODS
CI-1007 and a pharmacologically active metabolite, PD 147693 (M1), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and M1 were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis.


RESULTS
CI-1007 and M1 have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3-30 mg/kg p.o.) and on continuous avoidance in monkeys (0.6-1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 Cmax increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3-30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6-1.2 mg/kg, but corresponding plasma M1 Cmax values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a long-linear regression. In monkeys, CI-1007 ECe50, gamma, and Keo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr-1, respectively, calculated by the link model.


CONCLUSIONS
CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although M1 produces antipsychotic-like effects similar to CI-1007, the contribution of M1 to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.
Feng
M R
MR
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. FengR@AA.WL.COM
Corbin
A E
AE
Wang
Y
Y
Christoffersen
C L
CL
Wiley
J N
JN
Strenkoski
C A
CA
Tucker
E V
EV
Ninteman
F W
FW
Meltzer
L T
LT
Heffner
T G
TG
Wright
D S
DS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D004298:Dopamine / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012453:Saimiri
D014150:Antipsychotic Agents; C094391:PD 147693; C090025:1,2,3,6-tetrahydro-4-phenyl-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine