Pharmaceutical Chemistry Journal
Vol. 43, No. 8, 2009
INFLUENCE OF THE STRUCTURE OF SUBSTITUTED BENZODIAZEPINES ON THEIR PHARMACOKINETIC PROPERTIES A. G. Artemenko,1,* V. E. Kuz'min,1 E. N. Muratov,1 P. G. Polishchuk,1 I. Yu. Borisyuk,1 and N. Ya. Golovenko1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 8, pp. 27 – 35, August, 2009. Original article submitted August 9, 2007.
The influence of the structure of substituted benzodiazepines on their pharmacokinetic properties including the bioavailability, elimination half-life, clearance, and distribution volume in the human organism has been studied. The analysis was performed using the QSAR/QSPR method based on the Simplex representation of molecular structure. Completely adequate models capable of describing quantitatively the structure—pharmacokinetic properties relationship were obtained using the statistical methods of projection onto latent structures and multiple linear regression. Structural factors determining changes in the pharmacokinetic properties of substituted benzodiazepines are established on the basis of the obtained models. Key words: benzodiazepines, ADME, bioavailability, pharmacokinetic properties, QSAR/QSPR, Simplex representation.
The term “tranquilizer” was introduced into medical practice in 1957 in order to denote psychotropic agents used to treat neuroses, psychiatric stress, and fear [1, 2]. The first tranquilizer, the 1,4-benzodiazepine derivative chlordiazepoxide (librium) appeared on the pharmaceutical market in 1959. Its analog diazepam (valium) appeared in 1960. These became the basis of a broader group of psychotropic drugs. Today the number of compounds synthesized in various laboratories of the world is over 3,000. Of these, over 30 are drugs [3], among which phenazepam [4] and gidazepam [5] are produced domestically. Such a diverse set of drugs makes it possible to select the most suitable specific one. However, the physician must have the appropriate criteria (pharmacodynamics and pharmacokinetics) in order to declare that the drug has a certain advantage [6]. The pharmacodynamic criteria include the duration of action of the benzodiazepines, which fall into three groups: a) short-action of 2 – 10 h (oxazepazepam, temazepam, triazolam); b) medium-action of about 10 – 15 h (alprozalam, bromazepam, lorazepam); and c) long-action of 15 – 30 h (clobazam, clonazepam, diazepam, nitrazepam) [7]. The elimination half-life (t1/2) of benzodiazepines is a special pharmacokinetic parameter. It clearly divides them 1 *
Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, 65080 Odessa, Ukraine. e-mail:
[email protected].
into three groups: a) long half-life 48 h; b) medium, 24 – 48 h; and c) short, h [8]. We note also that clinical pharmacologists have recently linked the development of dependence on benzodiazepines to t1/2 [9]. The elimination half-life is closely related through the clearance (Cl) to other pharmacokinetic parameters such as the distribution volume (Vd) and the bioavailability (F). Vd
Absorption
Cl
t1/2
Administration time
F
Dosing regime
Dose
Drugs with a short t1/2 (alprozalam) are prescribed to patients in doses of 0.2 – 0.5 mg peroral 2 – 3 times per day; triazolam, 0.125 – 0.5 mg. For drugs with a medium t1/2 (diazepam), the dose is 2 – 10 mg 2 – 4 times per day; long (flunitrazepam, 15 – 30 mg; gidazepam, 20 – 50 mg), 3 times per day. These and other properties of benzodiazepine drugs make it critical to establish the quantitative relationship between their structure and pharmacokinetic properties in order 454 0091-150X/09/4308-0454 © 2009 Springer Science+Business Media, Inc.
Influence of the Structure of Substituted Benzodiazepines
455
Differentiation of atoms by nature O
O H3C O
O
+
H
+
+
+
+
O
...
O
N
N
N
N
N
H
O
+3
0.02
H
O
–0.18
Differentiation of atoms by charge
C
0.24
Breakdown into groups (A...G), depending on atomic charge:
E
A
E
0.02
C
0.02
–0.04
H
C
H
H
0.06
O
–0.21
0.02
H H
H
G F
0.12
A
E
A£–0.10
