Pharmacokinetic-Pharmacodynamic Correlation and Brain Penetration of sec-Butylpropylacetamide, a New CNS Drug Possessing Unique Activity against Status Epilepticus.

sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of the ability to block SE when given 20-60 min after the beginning of a seizure. However, intraperitoneal (i.p.) administration to rats cannot be extrapolated to humans. Consequently, in the current study a comparative pharmacokinetic (PK)-pharmacodynamic analysis of SPD was conducted following i.p., intramuscular (i.m.), and intravenous (i.v.) administrations to rats. SPD brain and plasma levels were quantified at various times after dosing following i.p. (60 mg/kg), i.v. (60 mg/kg), and i.m. administrations (120 mg/kg) to rats, and the major PK parameters of SPD were estimated. The antiseizure (SE) efficacies of SPD and its individual stereoisomers were assessed in the pilocarpine-induced BZD-resistant SE model following i.p. and i.m. administrations to rats at 30 min after seizure onset. The absolute bioavailabilities of SPD following i.p. and i.m. administrations were 76% (i.p.) and 96% (i.p.), and its clearance and half-life were 1.8-1.5 L h(-1) kg(-1) and 0.5-1.7 h, respectively. The SPD brain-to-plasma AUC ratios were 1.86 (i.v.), 2.31 (i.p.), and 0.77 (i.m.). Nevertheless, the ED50 values of SPD and its individual stereoisomers were almost identical in the rat pilocarpine-induced SE model following i.p. and i.m. administrations. In conclusion, in rats SPD is completely or almost completely absorbed after i.m. and i.p. administration and readily penetrates into the brain. Consequently, in spite of PK differences, the activities of SPD in the BZD-resistant SE model following i.m. and i.p. administrations are similar.

Warfarin metabolism and anticoagulant effect: a prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions.

BACKGROUND: Cytocbrome P450 (CYP) 2C9 polymorphism affects the warfarin dosage requirement in stable outpatients. However, it is not known whether the CYP2C9 genotype contributes to the variability in warfarin dosage in the presence of drug-disease and drug-drug interactions. OBJECTIVE: The aim of this study was to examine the effects of CYP2C9 genetic polymorphism on warfarin dosage requirements in patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin. METHODS: This prospective, observational study was conducted at Hadassah University Hospital, Jerusalem, Israel. Data from consecutive patients treated with warfarin for at least 3 months and admitted to the internal medicine ward were eligible for inclusion. Clinical data, international normalized ratio (INR), and warfarin dosage were recorded from medical records. The CYP2C9 genotype was determined using polymerase chain reaction restriction fragment length polymorphism, and plasma concentrations of (S)- and (R)-warfarin were determined by high-performance liquid chromatography using chiral methods. RESULTS: One hundred nineteen subjects (52% women) were studied. Mean age was 65.8 years (95% CI, 63.1-68.4), and weight was 74.9 kg (95% CI, 72.1-77.7). The mean warfarin dosage was 33% lower in patients with the CYP2C9-*1/*3 genotype (mean [SEM], 0.045 [0.006] mg/kg x d(-1)) compared with the CYP2C9-*1/*1 genotype (0.067 [0.004] mg/kg x d(-1)) (P=0.008); an intermediate value was found for the CYP2C9-*1/*2 genotype (0.062 [0.008] mg/kg x d(-1)). However, despite the lower dosage, INR was significantly higher in patients with the *1/*3 genotype (mean [95% CI], 3.29 [2.44-4.14]) (n=18) compared with the *1/*1 genotype (2.52 [2.34-2.71]) (n=64) (P=0.029). In addition to genotype, older age, congestive heart failure (CHF), and treatment with antibiotics were associated with lower warfarin dosages, whereas treatment with drug-metabolism inducers was associated with higher warfarin dosages. In addition, the ratios of (S)- to (R)-warfarin concentrations were significantly higher in patients with *1/*3 compared with those in patients with the *1/*1 genotype. CONCLUSIONS: In this study population of patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin, CYP2C9 *1/*3 genotype, older age, CHF, and the use of antibiotics were associated with lower warfarin dosage requirements. The CYP2C9*1/*3 genotype, compared with CYP2C9 *1/*1, was associated with 33% lower mean warfarin dosage requirements and higher INR values, which were higher than the upper therapeutic range of INR (ie, 3). Genetic CYP2C9 polymorphism contributed to the variability in warfarin dosage requirements in the presence of drug-disease and drug-drug interactions.

Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain.

Antiepileptic drugs (AEDs) are often utilized in the treatment of neuropathic pain. The major AED valproic acid (VPA) is of particular interest as it is thought to engage a variety of different neural mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but life-threatening side effects: teratogenicity and hepatotoxicity. We synthesized VPA's corresponding amide: valpromide (VPD), two of VPAs isomers and their corresponding amides; valnoctic acid (VCA), valnoctamide (VCD), diisopropyl acetic acid (DIA), diisopropylacetamide (DID), and VPD's congener: N-methyl-VPD (MVPD). VCD, DID and VPD are nonteratogenic, potentially nonhepatotoxic, and exhibit better anticonvuslant potency than VPA. In this study, we assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation model of neuropathic pain (SNL, Chung model). VCA and MVPD were inactive. However, VPD (20-100 mg kg(- 1)), VCD (20-100 mg kg(- 1)) and DID (20-90 mg kg(- 1)) produced dose-related reversal of tactile allodynia with ED50 values of 61, 52 and 58 mgkg(- 1), respectively. All the amides were more potent than VPA (ED50=269 mgkg(- 1)). The antiallodynic effect of VPA, VPD, VCD and DID was obtained at plasma concentrations of 125, 24, 18 and 7 mg l(- 1), respectively, with a good pharmacokinetic-pharmacodynamic correlation and a minimal lag response. VCD and DID were found to have minimal motor and sedative side effects at analgesic doses, and were equipotent to GBP, currently the leading drug in neuropathic pain treatment. Consequently, VCD and DID have potential to become new drugs for the treatment of neuropathic pain.

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents.

1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer-enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(-1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic PID also significantly increased the seizure threshold in this model. 5. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer-enantiomer interaction. 7. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer-enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.