Korbtham Sathirakul

Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers

Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2).

Pharmacokinetics of mitragynine in man

Background Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users. Methods Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic linearity and parameters reported are necessary pharmacological information of Kratom, and there is a possibility for it to be developed medically as a pain killer or better opioid substitute in the future.

Development of phyllanthin-loaded self-microemulsifying drug delivery system for oral bioavailability enhancement

Abstract Phyllanthin, a poorly water-soluble herbal active component from Phyllanthus amarus, exhibited a low oral bioavailability. This study aims at formulating self-microemulsifying drug delivery systems (SMEDDS) containing phyllanthin and evaluating their in-vitro and in-vivo performances. Excipient screening was carried out to select oil, surfactant and co-surfactant. Formulation development was based on pseudo-ternary phase diagrams and characteristics of resultant microemulsions. Influences of dilution, pH of media and phyllanthin content on droplet size of the resultant emulsions were studied. The optimized phyllanthin-loaded SMEDDS formulation (phy-SMEDDS) and the resultant microemulsions were characterized by viscosity, self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. In-vitro dissolution and oral bioavailability in rats of phy-SMEDDS were studied and compared with those of plain phyllanthin. Phy-SMEDDS consisted of phyllanthin/Capryol 90/Cremophor RH 40/Transcutol P (1.38:39.45:44.38:14.79) in % w/w. Phy-SMEDDS could be emulsified completely within 6 min and formed fine microemulsions, with average droplet range of 27–42 nm. Phy-SMEDDS was robust to dilution and pH of dilution media while the resultant emulsion showed no phase separation or drug precipitation after 8 h dilution. The release of phyllanthin from phy-SMEDDS capsule was significantly faster than that of plain phyllanthin capsule irrespective of pH of dissolution media. Phy-SMEDDS was found to be stable for at least 6 months under accelerated condition. Oral absorption of phyllanthin in rats was significantly enhanced by SMEDDS as compared with plain phyllanthin. Our study indicated that SMEDDS for oral delivery of phyllanthin could be an option to enhance its bioavailability.

In vitro-in vivo correlation study for the dermatopharmacokinetics of terbinafine hydrochloride topical cream.

Background: To investigate the relationship between dermatopharmacokinetic (DPK) tape stripping from in vitro and in vivo using 1% terbinafine hydrochloride topical cream as the model formulation. Methodology: In vitro and in vivo tape strippings were conducted on separated pig ear skin used as a biological membrane for franz diffusion cell testing and the non-hairy skin area at the ventral forearms of healthy volunteers, respectively. Terbinafine (1%) topical cream was applied to the skin for 0.5, 2, and 4 h. The drug profiles of terbinafine across the stratum corneum were determined immediately (time 0 h), and at 0.5, 1, 2, and 4 h after removing the formulation. The amounts of terbinafine were analyzed by a validated high-performance liquid chromatography-ultraviolet method. The area under the curve (AUC) and the maximum amounts of terbinafine absorption (Qmax) were obtained from pharmacokinetic software. Partition coefficient (KSC/veh) and diffusion parameter (D/L2) were derived from the Fick’s second law equation. During the schedule time of 8 h, the deviations of in vitro and in vivo data were 6.61 and 30.46% for AUC and Qmax, respectively. There was insignificant difference of the KSC/veh and the D/L2 between excised pig ear and human skin. In addition, KSC/veh and D/L2 at Tmax of 2 h were used to predict the AUC presented the value of 4.7481 %h whereas the true value calculated from pharmacokinetic software provided the value of 5.9311 %h differing from each other in approximate of 20%. Conclusions: In vitro tape stripping using the separated pig ear skin as a viable membrane of the franz diffusion cell testing demonstrates the potential to represent in vivo tape stripping in human for topical bioavailability/bioequivalence study of terbinafine hydrochloride 1% topical cream.

Elucidation of the natural artemisinin decomposition route upon iron interaction: a fine electronic redistribution promotes reactivity

The conformational analysis of artemisinin by molecular dynamics and quantum chemistry calculations revealed the existence of seven energy minima with specific interconversion pathways. Among the seven conformers, only , and were able to undergo bond rearrangements upon Fe(2+) interaction. These rearrangements were due to a peculiar puckering of the trioxane ring that brings its three oxygen atoms in an ideal geometrical position for interacting with Fe(2+) ions, promoting an electronic redistribution in the molecule. A rapid molecule rearrangement led to a stable energy minimum structure with an additional ring that is similar to a plant metabolite. Our results suggest an alternative pathway for generating toxic radical chemical species for the malaria parasite, where artemisinin is not toxic by itself but rather is an intermediate for molecular partners that generate radical structures deleterious for the parasite proteins, after electron transfers from the Fe(2+)/artemisinin complex.

Dermal Pharmacokinetics of Terpinen-4-ol Following Topical Administration of Zingiber cassumunar (plai) Oil

The purpose of this study was to investigate dermal pharmacokinetics of terpinen-4-ol in rats following topical administration of plai oil derived from the rhizomes of Zingiber cassumunar Roxb. Unbound terpinen-4-ol concentrations in dermal tissue were measured by microdialysis. The dermal pharmacokinetic study of terpinen-4-ol was performed under non-occlusive conditions. The oil was topically applied at a dose of 2, 4, and 8 mg/cm2 plai oil corresponding to the amount of 1.0, 1.9, and 3.8 mg/cm2 terpinen-4-ol, respectively. Following topical application of the oil, terpinen-4-ol rapidly distributed into the dermis and demonstrated linear pharmacokinetics with no changes in the dose-normalized area under the concentration-time curves across the investigated dosage range. The mean percentages of free terpinen-4-ol distributed in the dermis per amount of administered were 0.39 ± 0.06 %, 0.41 ± 0.08 %, and 0.30 ± 0.03 % for 2, 4, and 8 mg/cm2 doses, respectively. The dermal pharmacokinetics of terpinen-4-ol could provide information for its further formulation development and therapy schedules.

A randomized, open-label, 2-period, crossover bioequivalence study of two oral formulations of 75 mg oseltamivir in healthy Thai volunteers.

AIM Oseltamivir, an ester prodrug of its active carboxylate metabolite, is an effective neuraminidase inhibitor used to treat influenza A and B virus infections. The purpose of this study was to compare the bioavailability of two 75 mg oral formulations of oseltamivir: a generic drug, GOP-A-Flu (test, Government Pharmaceutical Organization, Thailand) and Tamiflu (reference, Hoffmann-La Roche Ltd., Nutley, NJ, USA) in healthy volunteers. SUBJECTS AND METHODS A single-dose, randomized, 2-sequence, crossover study was conducted in 24 healthy Thai volunteers. Each volunteer received a 75 mg capsule of the reference or test drugs under fasting conditions. Blood samples were collected before dosing and at various time points up to 48 hours after dosing and analyzed for plasma oseltamivir and oseltamivir carboxylate concentrations. The pharmacokinetic parameters including Cmax, AUC0-t, AUC0-infinity, tmax and t1/2 were analyzed using the non-compartmental method. Drug safety was assessed. RESULTS 23 volunteers completed both treatment periods. The geometric mean ratios (test/reference) between the two formulations of oseltamivir were 96.83% (90% CI, 76.85 - 123.15%) for Cmax 103.66% (86.44 - 113.56%) for AUC0-t, and 103.98% (86.44 - 113.56%) for AUC0-infinity. Those of oseltamivir carboxylate were 102.17% (90% CI, 90.90 - 109.10%) for Cmax, 103.95% (90.90 - 109.10%) for AUC0-t, and 103.95% (90.92 - 109.08%) for AUC0-infinity. No significant difference of the tmax of oseltamivir and oseltamivir carboxylate between the two formulations was detected (p > 0.05). Both formulations were well-tolerated. CONCLUSION Although the Cmax of oseltamivir was the only parameter not entirely within the equivalence criteria, the two capsule formulations were considered bioequivalent in terms of rate and extent of absorption regarding its active carboxylate metabolite.

Chitosan‑based nanoparticles with damnacanthal suppress CRM1 expression

Cancer is one of the leading causes of mortality worldwide. Phytochemicals may be promising anticancer agents given their various chemical structures and diverse biological activities. Damnacanthal (DAM) is a major bioactive component of Noni, which has been investigated previously as a cancer-preventive or chemotherapeutic agent. DAM has also been reported to exhibit anti-proliferative activity in several cancer types. In the present study, it was identified that DAM downregulates chromosome maintenance protein 1 (CRM1) expression in human cancer cells. The application of chitosan-based nanoparticles (NPs) with DAM also induced CRM1 downregulation, which suggests that chitosan-based NPs may be effective vehicles for delivery of phytochemicals such as DAM. It was also identified that DAM increased the levels of the tumor suppressor non-steroidal anti-inflammatory drugs-activated gene 1 in the nucleus, thereby leading to enhanced anticancer effects. The results of the present study indicate that DAM and its nanoformulation may be a candidate anticancer drug.