Influence of γ-aminobutyric acid on baclofen intestinal absorption

Since previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by β-alanine and therefore mediated, at least in part, by the β-aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a γ-aminoacid model compound, γ-aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease as the GABA concentration increases, with a limiting value of 0.65 h^?1 (±0.01). A partial competitive inhibition or complete competitive inhibition in the presence of a passive component could define the interaction phenomena between the two substances. Kinetic absorption parameters for GABA in the presence and absence of baclofen (K_i = 5.67 ± 1.54, K_m = 3.87 ± 0.63) suggest the existence of more than one intestinal carrier system for baclofen or GABA.     

Influence of leucine on intestinal baclofen absorption as a model compound of neutral α-aminoacids

The inhibitory effect of the essential α-aminoacid L-leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of an in situ rat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5–100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations, however, did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component, K = 0.35 (±0.08)h^?1, K_i = 0.25 (±0.09)mM, AIC= ?97.02. In the light of some of the absorption features of the drug, however, the residual absorption of baclofen in the presence of high leucine concentrations should be attributed to another transport system not used by leucine. Apparent parameters characterizing absorption of leucine in the presence of baclofen (0.5mM) were V_m=61.02 (±5.46)mM h^?1; K_m=8.04 (±0.89)mM, and AIC=62.25. The results indicate that baclofen and leucine share some carriers in the intestinal absorption processes. Since leucine is an essential dietary aminoacid, and therefore a normal food component, this finding could be relevant in preventing interactions that would lead to a reduced oral bioavailability during baclofen therapy.     

Studies on GABA release in vivo using a simple method for perfusion of the fourth ventricle of the rat

A simple _{in vivo} method for perfusion of the fourth ventricle of the anaesthetized rat is described in detail. After loading the cerebellum and other tissues bordering the fourth ventricle with [¹⁴C]-GABA its efflux was monitored over a period of time and depolarizing stimuli or drugs applied. Useful information has thus been obtained of the possible value of this technique in studying neurotransmitter release and of the in vivo release characteristics of GABA. Iso-osmotic artificial cerebrospinal fluid (ACSF), containing 50 mM potassium produced a calcium-dependent increase in the efflux of radioactivity (80% of which was present as GABA) and addition of β-alanine (5 × 10^?5 M and 5 × 10^?4m) to the ACSF, to block the re-uptake of GABA, increased the spontaneous efflux of GABA. β-alanine (5 × 10^?4m) also augmented the potassium-stimulated efflux of GABA.     

Intestinal Absorption Studies on Peptide Mimetic α-Methyldopa Prodrugs

Two dipeptide mimetic prodrugs, 1 and 2 , and two tripeptide mimetic prodrugs, 3 and 4 , of l -α-methyldopa were evaluated for intestinal absorption by in-situ single-pass rat jejunal perfusion studies and by in-vitro uptake experiments in brush-border membrane vesicles (BBMVs) prepared from rat intestine. In the perfusion studies, compound 1 demonstrated a 3.5-fold increase in permeability (P_m* = 2.27) as compared with that of α-methyldopa (P_m* = 0.65), indicating that this prodrug was better absorbed in the intestine than its parent drug. Other prodrugs showed no significant improvement in intestinal permeability. The results correlated with the results of BBMV uptake studies. In the presence of an inward proton gradient, compound 1 showed Michaelis-Menton saturable kinetics of BBMV uptake with a low value of K_m (0.06 ± 0.13 mm ) and a high value of V_max/K_m (36.38 nmol (mg protein)^?1/30 s mm ^?1) at a low concentration range and a linear uptake at high concentrations with K_d = 0.14 ± 0.02 mm . Compounds 2 and 3 were mainly taken up in BBMVs via passive diffusion. Compound 4 was taken up in BBMVs basically via the carrier-mediated transport system, while the rate of uptake was much lower than that of compound 1 . The uptake of compounds 1 and 4 was significantly inhibited by dipeptides l -Gly-l -Pro and l -Gly-l -Phe, and cephradine, a β-lactam known to be transported via the dipeptide carrier system, indicating that both compounds were taken up in BBMVs via the H⁺-coupled dipeptide-mediated transport system. In contrast to the complicated uptake profile of α-methyldopa, the higher rate of BBMV uptake with less variation demonstrated on compound 1 suggested that the attached nonessential amino acid moiety, d -phenylglycine, is a feasible delivery tool in carrying the parent drug through the intestine.     

Characterization of [3H]muscimol binding to mouse brain membranes.

The binding of [³H]muscimol {[methylene-³H(N)]-3-hydroxy-5-aminoethyl isoxazole} to a membrane fraction from mouse brain was studied as a possible model for the GABA recognition site of the γ-aminobutyric acid (GABA)-anionophore receptor complex. Kinetic studies showed two distinct association and dissociation rate constants, 2.3 × 10^?4 and 1.4 × 10^?5 sec^?1 nM^?1 for association and 1.2 × 10^?2 and 1.0 × 10^?3 sec^?1 for dissociation. Equilibrium analysis (Scatchard plot) of binding data also indicated two types of sites with K_D equal to 9 × 10^?9 and 70 × 10^?9 M. Detergents (0.1% Triton X-100, 0.1% Lubrol PX or 5% Tween 20) had no effect on the binding of [³H]muscimol or other conformationally restricted agonists such as imidazoleacetic acid, isoguvacine, THIP (4,5,6,7-tetrahydroisoxazole [5,4-c] pyridine-2-ol), and (±)-isonipecotic acid. In contrast to this, the detergents potentiated the ability of the less conformationally restricted agonists such as GABA and β-alanine in displacing [³H]muscimol. Binding of bicuculline was reduced by all of the detergent treatments.     

Physicochemical characteristics and gastrointestinal absorption behaviors of S-propargyl-cysteine,a potential new drug candidate for cardiovascular protection and antitumor treatment

Abstract

1. As a potential new drug candidate for cardiovascular protection and antitumor treatment, the physicochemical properties, gastrointestinal (GI) absorption behaviors and mechanisms of S-propargyl-cysteine (SPRC) were investigated in this study.

2. SPRC exhibited favorable solubility in aqueous media. The log P and log D values were low (≤1.93?±?0.08). The pK_a in the acidic and basic regions was 2.08?±?0.02 and 8.72?±?0.03, respectively. The isoelectric point was 5.40?±?0.02. SPRC was stable in the rat GI fluids, and showed no obvious adsorption and metabolism in the rat GI tract.

3. SPRC displayed poor gastric absorption and favorable intestinal absorption in the rat in situ GI perfusion model. Absorption rate constants (k_a), hourly absorption percentage (P) and apparent permeability coefficient (P_app) of SPRC in the small intestine were ≥0.77?±?0.06?h^?1, 59.25?±?4.02% and (7.99?±?0.88)?×?10^?5?cm/s, respectively. Absorption of SPRC exhibited a certain dependence on physiological pH and absorption region. Absorption of SPRC was not inhibited by l-methionine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid.

4. SPRC showed favorable oral absorption. It can be categorized as a BCS class I drug. The membrane pore transport appeared to be one of the predominant absorption modes for SPRC.     

Baclofen (β-p-chlorophenyl-γ-aminobutyric acid) enhances [3H]γ-aminobutyric acid (3H-GABA) release from rat globus pallidus in vitro

The rat globus pallidus has been investigated as a possible model in which to study pre-synaptic G AB A mechanisms in vitro. (±)-Baclofen (300 μM-1 mM) significantly enhanced the release of radioactivity from superfused slices of rat globus pallidus prelabelled with ³H-GABA in vitro. This releasing action was specific to the (+)-isomer of baclofen: neither the (—)-isomer nor another neuronal depressant DL-α-∞-diaminopimelic acid had any significant effect. The releasing effect of baclofen appeared unrelated to the phenethylamine moiety of its structure as neither β–phenethylamine nor dopamine evoked release of ³H-GABA from pallidal slices. Baclofen increased the efflux of radioactivity from pallidal slices prelabelled with either [³H]β-alanine or [³H]diaminobutyric acid in vitro. The use of specific glial and neuronal GABA uptake blocking compounds (β-alanine and (±)-cis-1,3-amino-cyclohexanecarboxylic acid) did not permit resolution of the elements from which baclofen was evoking [³H]GABA release. Baclofen also inhibited uptake of [³H]GABA into pallidal slices with an IC50 value of 6 × 10^?4 M. The GABA-like properties of baclofen may be related to the (+)-isomer while non-specific neuronal depressant actions are an effect of the (—)-isomer. The potential of the (+)-isomer as an antipsychotic agent while (—)-baclofen remains the effective antispastic drug free from unwanted side-effects, is discussed.     

Conformational investigation of α, β-dehydropeptides

The crystal structure of Ac-Pro-ΔVal-NHCH₃ was examined to determine the influence of the α,β-dehydrovaline residue on the nature of peptide conformation. The peptide crystallizes from methanol-diethyl ether solution at 4° in needle-shaped form in orthorhombic space group P2₁2₁2₁ with a= 11.384(2) Å, b = 13.277(2) Å, c = 9.942(1) Å. V = 1502.7(4) ų Z = 4, D_m= 1.17 g cm^?3 and D_c=1.18 g cm^?3 The structure was solved by direct methods using SHELXS-86 and refined to an R value of 0.057 for 1922 observed reflections. The peptide is found to adopt a β-bend between the type I and the type III conformation with φ₁=?68.3(4)°, ψ₁=? 20.1(4)°, φ₂=?73.5(4)°= and Ψ₂=?14.1(4)°=. An intramolecular hydrogen bond between the carbonyl oxygen of ith residue and the NH of (i+ 3)th residue stabilizes the β-bend. An additional intermolecular N.,.O hydrogen bond joins molecules into infinite chains. In the literature described crystal structures of peptides having a single α,β-dehydroamino acid residue in the (i+ 2) position and forming a β-bend reveal a type II conformation.     

Disposition and bioavailability of the β1-adrenoceptor antagonist talinolol in man

In an open randomized crossover study, the pharmacokinetics and bioavailability of the selective β₁-adrenoceptor antagonist talinolol (Cordanum®—Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC-MS. At the end of infusion a peak serum concentration (C_max) of 631 ± 95 ng mL^?1 (mean ± SD) was observed. The area under the serum concentration-time curve from zero to infinity (AUC_0-∞) was 1433 ± 153 ng h mL^?1. The following parameters were estimated: terminal elimination half life (t_1/2), 10.6 ± 3.3 h; mean residence time, 11.6 ± 3.1 h; volume of distribution, 3.3 ± 0.5 L kg^?1; and total body clearance, 4.9 ± 0.6 mL min^?1 kg^?1. Within 36 h 52.8 ± 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 ± 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a C_max of 168 ± 67 ng mL^?1 was reached after 3.2 ± 0.8h. The AUC_0-∞ was 1321 ± 382 ng h mL^?1. The t_1/2 was 11.9 ± 2.4 h. 28.1 ± 6.8% of the dose or 55.0 ± 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 ± 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 ± 15% (95% confidence interval, 36–69%). Talinolol does not undergo a relevant first-pass metabolism, and its reduced bioavailability results from incomplete absorption. Talinolol disposition is not found to be altered in poor metabolizers of debrisoquine type.     

Systemic absorption of ocular pilocarpine is modified by polymer matrices

Systemic absorption of ocularly applied pilocarpine (1.2 mg) was studied after administration in aqueous solution, in hydroxypropylcellulose (HPC) matrix, and in a matrix of n-butyl half-ester of poly(methyl vinyl ether/maleic anhydride) (PVM/MA). In vitro release of pilocarpine from the HPC-matrix deviated slightly and positively from the diffusional square root of time dependence. The rate of drug release was independent of the phosphate buffer concentration of the dissolution medium with an initial pH of 7.4; the rate of release was 10.91 ± 0.59% min^?0.5 in 1.3 mM buffer and 9.91 ±0.37% min^?0.5 in 66.7 mM buffer. A matrix of n-butyl half-ester of PVM/MA released pilocarpine according to zero-order kinetics. The rate of drug release was 0.22 ± 0.02% min^?1 in 1.3 mM phosphate buffer and 0.95 ± 0.06% min^?1 in 66.7 mM phosphate buffer. From the 2% aqueous solution, pilocarpine was absorbed efficiently into the plasma (t_max = 3.6 ± 0.9 min, c_max = 0.384 ± 0.024 μg/ml). Pharmacokinetic analysis of data for drug absorption revealed that the conjunctiva of the eye was the most important site for systemic absorption of pilocarpine. Both the HPC matrix (t_max = 35.0 ± 7.9 min, c_max = 0.256 ± 0.022 μg/ml) and the matrix of n-butyl half-ester of PVM/MA (t_max = 204 ± 17.5 min, c_max = 0.112 ± 0.014 μg/ml) delayed and decreased the peak concentrations of pilocarpine in general circulation. (AUC_{0–6 h}/AUC_{0–6 h,i,v.}) values were 0.72 ± 0.08, 0.67 ± 0.16, and 0.41 ± 0.05 for the aqueous solution, HPC matrix, and n-butyl half-ester of PVM/MA matrix, respectively. During the in vivo study, HPC matrices dissolved in 7–12 min in the tear fluid. n-Butyl half-ester of PVM/MA neither dissolved totally nor released all the drug from the matrix in the tear fluid during 8 h. Besides improving ocular drug absorption, as shown in earlier studies, the pilocarpine concentrations in systemic circulation can be decreased by administering the drug in polymer matrices.     

CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement

1.?The individual cytochrome P450 isoforms in dextropropoxyphene N-demethylation to nordextropropoxyphene were determined and the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in cytochrome P4502D6 (CYP2D6) extensive (EM) and poor (PM) subjects were characterized.

2.?Microsomes from six CYP2D6 extensive metabolizers and one CYP2D6 poor metabolizer were used with isoform specific chemical and antibody inhibitors and expressed recombinant CYP enzymes. Groups of three CYP2D6 EM and PM subjects received a single 65-mg oral dose of dextropropoxyphene, and blood and urine were collected for 168 and 96 h, respectively.

3.?Nordextropropoxyphene formation in vitro was not different between the CYP2D6 extensive metabolizers (K_m = 179 ± 74 μM, Cl_int = 0.41 ± 0.26 ml mg^?1 h^?1) and the PM subject (K_m = 225 μM, Cl_int = 0.19 ml mg^?1 h^?1) and was catalysed predominantly by CYP3A4. There was no apparent difference in the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in CYP2D6 EM and PM subjects.

4.?CYP3A4 is the major CYP enzyme catalysing the major metabolic pathway of dextropropoxyphene metabolism. Hence variability in the pharmacodynamic effects of dextropropoxyphene are likely due to intersubject variability in hepatic CYP3A4 expression and/or drug–drug interactions. Reported CYP2D6 phenocopying is not due to dextropropoxyphene being a CYP2D6 substrate.     

Hepatic metabolism of diallyl disulphide in rat and man

1.?The metabolism of diallyl disulphide was investigated in vitro with rat and human liver cell subfractions and ex vivo with an isolated perfused rat liver.

2.?Diallyl disulphide was oxidized to diallylthiosulphinate by rat liver microsomes with an apparent K_m = 0.86 ± 0.1?mM and an apparent V_max = 0.47 ± 0.12 nmol?min^?1?mg^?1 protein (mean ± SE). Both cytochrome P450 (CYP) and flavin-containing monooxygenases were involved, with CYP2B1/2 and CYP2E1 being the most active CYP enzymes.

3.?In rat and man, microsomal oxidation of allylmethyl sulphide to allylmethyl sulphoxide and allylmethyl sulphone also occurred, although at a low rate. Diallyl disulphide was also metabolized to allylglutathione sulphide and allylmercaptan. In addition, diallylthiosulphinate reacted non-enzymatically with glutathione to form allylglutathione sulphide.

4.?When an isolated rat liver was perfused with diallyl disulphide, the metabolites allyl mercaptan, allylmethyl sulphide, allylmethyl sulphoxide, allylmethyl sulphone and allylglutathione sulphide were detected primarily within the liver tissue, with only small amounts of metabolites found in the bile and perfusion medium. The pharmacokinetic parameters for diallyl disulphide were t_1/2 = 6.09?min; AUC_0–∞ = 4.77?min?mmol?l^?1; clearance = 34.22 ml?min^?1.

5.?A scheme for the metabolism of diallyl disulphide in rat and man is proposed.     

Inhibition of intestinal water and electrolyte absorption by senna derivatives in rats

Three intestinal segments were simultaneously perfused with Tyrode solution in the anaesthetized rat using a perfusion rate of 12 ml h^?1. Dried purified senna extract containing 60% Ca-sennosides A + B (I) administered with the perfusion fluid had no or only minimal effects on intestinal absorption. Large doses (4 g litre^?1) slightly reduced net Na, CI and H₂O absorption predominantly in the colon and the ileum; the jejunum was unaffected. Dried purified senna extract containing 18% oxidized Ca-sennosides (II) reduced net Na, Cl and H₂O absorption in all three intestinal segments, the effects increasing from the jejunum to the colon. Large doses (4 g litre^?1) induced net Na and H₂O secretion. II being administered with the colon perfusion fluid affected H₂O and electrolyte absorption in the colon and to a lesser degree, in the ileum. Pure rhein (III, 0·28 g litre^?1) had similar effects to II. Pure sennosides A + B (IV, 2 g litre^?1) had no effect on intestinal absorption. These results confirm that changes in the absorptive behaviour of the gut mucosa are, at least partly, responsible for the laxative action of anthraquinone drugs and that this effect is mainly dependent on the presence of oxidized derivatives. There is evidence that the drug's effect is not locally restricted to the colon as is seen from the ileal response after intracolonic administration. Side-effects like griping which are sometimes observed after senna treatment seem to originate from motility changes rather than from changes in absorption.     

Pharmacokinetics of intravenous and epidural ropivacaine in the rhesus monkey

Ropivacaine is a new long-acting amide local anesthetic which is possibly less cardiotoxic than bupivacaine. The absorption and disposition of ropivacaine were characterized in six rhesus monkeys in an open two-way crossover study following intravenous and epidural administration. For these studies, animals were anesthetized for placement of intravenous and intraarterial catheters. For the epidural studies, a PE-10 catheter was also inserted 3 cm into the lumbar epidural space. After recovery from anesthesia, animals received ropivacaine 1 mg kg^?1 intravenously over 1 min or 10 mg of ropivacaine epidurally (two 1 ml doses of 0.5, 5 min apart), and arterial blood samples were obtained over 5 h. Serum ropivacaine concentrations were determined by gas chromatography with NP detection. Concentration—time data following i.v. and epidural administration were fitted simultaneously. Initial parameter estimates were obtained by analyzing each route separately. Input rates and their corresponding extent of absorption were estimated using deconvolution. Mean (±SD) disposition parameters included: V_ss = 1.11±0.198 1kg^?1; CL = 0.711 ± 0.158 1 h^?1 kg^?1; t_1/2,z = 2.07 ± 0.438 h. Mean (± SD) absorption parameters included: F₁ = 0.506 ± 0.221; t = 0.060 ± 0.078 h; F₂ = 0.444 ± 0.182; t = 6.45 ± 11.09h. Ropivacaine's biphasic absorption and bioavailability are similar to those of other amide local anesthetics. The biphasic absorption may be related to partitioning into fat or regional changes in blood flow induced by the drug.     

Carrier-mediated intestinal absorption of valacyclovir,the L-valyl ester prodrug of acyclovir. 1. Interactions with peptides,organic anions and organic cations in rats

The mechanism of intestinal transport of valacyclovir (VACV), the L-valyl ester prodrug of acyclovir, was investigated in rats using an in situ intestinal perfusion technique. VACV demonstrates an oral bioavailability that is three to five time greater than acyclovir, concentration dependent, and saturable in humans. Homogenate and perfused buffer stability results demonstrated that VACV was increasingly unstable with increasing pH. VACV was converted to ACV in a concentration dependent manner during a single pass through the intestinal segment. Perfusions were performed at 37°C, pH 6.5, and under iso-osmotic conditions (290±10 mOsm L⁻¹). Intestinal outlet concentrations were corrected for VACV that was converted to ACV during the perfusion. The effective dimensionless intestinal permeability (P_e*) of VACV was concentration dependent, saturable (intrinsic K_m = 1.2±0.7 mM), and significantly reduced (p <0.05) in the presence of peptide analogues (amoxicillin, ampicillin, cefadroxil, and cephradine), by the organic anion, p -amino hippuric acid and by the organic cation quinine. VACV transport was not inhibited by classical nucleoside competitive substrates or inhibitors or by valine. These results suggest that H⁺–oligopeptide, H⁺–organic cation, and organic anion transporters are involved in the small-intestinal uptake of VACV. The permeability of VACV in the colon was very low, indicating that VACV is predominantly absorbed from the small intestine. VACV P_e* was not altered in the presence of glucose-induced convective fluid flow, suggesting that carrier-mediated, transcellular uptake is the predominant absorption pathway of VACV in rat small intestine. Based on these results, the oral bioavailability of VACV appears to be significantly influenced by the preabsorptive conversion of VACV to the poorly absorbed ACV, by the involvement of multiple transporters in VACV small-intestinal uptake, and by the low permeability of VACV in the colon. © 1998 John Wiley & Sons, Ltd.     

Cis-resveratrol glucuronidation kinetics in human and recombinant UGT1A sources

1. It was hypothesized that cis-resveratrol glucuronidation contributes to a greater extent to in-vitro disposition of total resveratrol than previously assumed. To this end, the kinetic data for cis-resveratrol glucuronidation are reported.

2. Glucuronidation assays were conducted in human liver and intestinal microsomes and in uridine diphosphate-glucuronosyltransferases (UGTs) UGT1A1, UGT1A6, UGT1A9, and UGT1A10. Kinetic parameters were estimated for the major cis-resveratrol-3-O-glucuronide (cis-R3G). Substrate inhibition was observed with apparent V_max, K_m and K_i of 6.1?±?0.3/27.2?±?1.2 nmol min^?1 mg^?1, 415?±?48.1/989.9?±?92.8 and 789.6?±?76.3/1012?±?55.9?μM in human intestinal microsomes (HIMs) and UGT1A6, respectively (estimate?±?standard error (SE)). Biphasic kinetics were observed in human liver microsomes (HLMs), while sigmoidal kinetics were seen in UGT1A9 (V_max?=?11.92?±?0.2 nmol min^?1 mg^?1; K_m?=?360?μM; n?=?1.27?±?0.07). The 4′-O-glucuronide (cis-R4′G) exhibited atypical kinetics in HLM, HIM, UGT1A1, and UGT1A10. UGT1A9 catalysed cis-R4′G formation at high substrate concentrations (V_max?=?0.33?±?0.015 nmol min^?1 mg^?1; K_m?=?537.8?±?67.8?μM).

3. In conclusion, although the rates of formation of cis-R3G in HLM and UGT1A9 were higher than those for trans-R3G, the contribution to total resveratrol disposition could not be determined fully due to atypical kinetics observed.

     

Pharmacokinetics of the γ-Aminobutyric Acid Agonist THIP (Gaboxadol) Following Intramuscular Administration to Man,with Observations in Dog

Abstract: The pharmacokinetics of the γ-aminobutyric acid (GABA) agonist, THIP (Gaboxadol) has been studied following intramuscular administration of 10 or 20 mg THIP-monohydrate to six healthy human volunteers. Additional experiments with special reference to the possible occurrence of non-linear kinetics and to estimation of the efficiency of absorption were carried out in three beagle dogs. As estimated from the dogs, absorption of THIP from the site of injection was efficient (F=0.94±0.16, mean±S.D., in 8 experiments). The time course of the THIP serum concentration was in all experiments adequately described by an open 1-compartment linear model. In most individual experiments a near maximum concentration was present at 15 or 10 min. after the administration to man and dog, respectively. In some subjects and dogs an uncertain relation was found between dose and the time integral of the THIP serum concentration, but the mode of variation did not suggest deviations from first-order kinetics at high doses or concentrations. The rate constant of elimination was estimated to 0.50±0.13 hr^?1 and 0.52±0.13 hr^?1 following injection of a 10 or 20 mg dose, respectively, to man (mean±S.D., n=6), and similar values were obtained from the dogs.     

Effect of grapefruit juice and food on the pharmacokinetics of pirfenidone in healthy Chinese volunteers: a diet–drug interaction study

1.?Ingestion of grapefruit juice and food could be factors affecting the pharmacokinetics of pirfenidone, a promising drug for treatment of idiopathic pulmonary fibrosis.

2.?A randomized, open-label, three-period crossover study was carried out in 12 healthy Chinese male volunteers who were randomized to one of the three treatments: pirfenidone tablets (0.4?g) were orally administered to fasted or fed subjects, or with grapefruit juice. The washout period was 7 d.

3.?Significantly reduced maximum plasma concentration (C_max, 5.0 5?±?1.39 versus 10.9 0?±?2.94?mg·L^{? 1}), modestly affected area-under-the-plasma concentration–time curve (AUC) from time zero to 12?h post dosing (AUC_0–12?h, 21.8 9?±?6.47 versus 26.1 6?±?7.32?mg·h·L^{? 1}) and delayed time to reach C_max (T_max) were observed in fed group compared with fasted group. Similar effects on C_max (5.8 2?±?1.23 versus 10.9 0?±?2.94?mg·L^{? 1}) and AUC_0–12?h (modest but not statistically significant, 24.4 4?±?7.40 versus 26.1 6?±?7.32?mg·h·L^{? 1}) were observed for grapefruit juice compared to fasted subjects.

4.?Co-administration of pirfenidone with grapefruit juice resulted in modestly reduced overall oral absorption and significantly reduced peak concentrations compared to fasting, which was similar to effect of food ingestion. No adverse events were observed in the study, but relatively dramatic reduction of peak concentrations should raise concerns for clinical efficacy and safety.     

Characterisation of [3H]gabapentin binding to a novel site in rat brain: homogenate binding studies

The binding characteristics of [³H]gabapentin, the radiolabelled analogue of the novel anticonvulsant gabapentin (1-(aminomethyl)cyclohexaneacetic acid) were studied using purified synaptic plasma membranes prepared from rat cerebral cortex. In 10 mM HEPES buffer [³H]gabapentin bound to a single population of sites with high affinity (K_D = 38 ± 2.8 mM) with a maximum binding capacity of 4.6 ± 0.4 pmol/mg protein, reaching equilibrium after 30 min at 20°C. This novel site was unique to the central nervous system with little or no specific [³H]gabapentin binding being measurable in a range of peripheral tissues. Binding was potently inhibited by a range of gabapentin analogues and 3-alkyl substituted γ-aminobutyric acid (GABA) derivatives although GABA itself and the selective GABA_B receptor ligand baclofen, were only weakly active. Gabapentin itself (IC₅₀ = 80 nM) and 3-isobutyl GABA (IC₅₀ = 80 nM) which also has anticonvulsant properties, showed the highest affinity for the binding site. Of a wide range of other pharmacologically active compounds only the polyamines spermine and spermidine influenced [³H]gabapentin binding, with both compounds producing a maximum of 50% inhibition of specific binding. Magnesium ions produced a similar pattern of inhibition but the effect of the polyamines and magnesium ions were not additive. The data provide evidence for the existence in brain of a novel binding site that may mediate the anticonvulsant effects of gabapentin and other potential anticonvulsant compounds.     

PLASMA LEVELS FOLLOWING SINGLE INTRAVENOUS, ORAL AND MULTIPLE ORAL DOSAGE IN NORMOTENSIVE AND HYPERTENSIVE SUBJECTS

1. The pharmacokinetics of methyldopa after oral and intravenous administration was studied in hypertensive and normotensive patients. After intravenous administration methyldopa plasma concentrations decayed according to a two-compartment open model. 2. For intravenous administration the overall elimination constant K_e1 was 0.56 ± 0.03 h^?1, the volume of distribution of the central compartment 0.29±0.08 1 kg^?1 and the plasma clearance rate 11.2±0.6 1 h^?1. 3. Plasma half-times during the β-phase of the methyldopa plasma decay curve following intravenous and oral administration were 2.8±1.3 and 2.1±0.7 h, respectively. 4. Maximal plasma levels in hypertensive out-patients show great variation and range from 0 to 1.9 μg ml^?1. 5. No relationships were found between maximal methyldopa plasma levels in patients under treatment and control of hypertension.