Koujirou Yamamoto

Comparative pharmacokinetic/pharmacodynamic analysis of proton pump inhibitors omeprazole, lansoprazole and pantoprazole, in humans

SummaryThe relationship between plasma concentrations and inhibitory effects on gastric acid secretion by proton pump inhibitors (PPIs) omeprazole (OPZ), lansoprazole (LPZ) and pantoprazole (PPZ), was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model in humans. The estimated values of apparent reaction rate constant of PPI and H+, K+-ATPase (K) were 1.34±0.17 (μM−1. h−1), 0.339±0.002 and 0.134±0.006 for OPZ, LPZ and PPZ, respectively. The estimated values of apparent turn-over rate constant of H+, K+-ATPase (k) were 0.0252±0.0019 (h−1), 0.0537±0.0006 and 0.0151±0.0002 for OPZ, LPZ and PPZ, respectively. The apparent dissociation constants of the H+, K+-ATPase-PPI complex (k/K.fp) corrected with plasma free fraction (fp) were about 1 nM for OPZ and LPZ and 2.3 nM for PPZ. Therefore, the potency of the inhibitory effect of PPZ on acid secretion may be slightly weaker than that of OPZ or LPZ. The apparent half lives (In2/k) of the inhibitory effect on acid secretion were 12.9 h for LPZ, <27.5 h for OPZ, and <45.9 h for PPZ, the recovery rate of the inhibitory effect of PPZ on acid secretion was slowest among these PPIs. In conclusion, the relationship between plasma concentrations and inhibitory effects of PPIs on gastric acid secretion could be analyzed by the PK/PD model.

Quantitative determination of domperidone in rat plasma by high-performance liquid chromatography with fluorescence detection

A sensitive and selective analytical method for the determination of domperidone in rat plasma is described. The procedure involves liquid-liquid extraction followed by reversed-phase high-performance chromatographic analysis with fluorometric detection at 282 nm for excitation and 328 nm for emission. The detection limit was 1 ng ml(-1) using 1 ml of plasma. This assay procedure should be useful for the pharmacokinetic study of domperidone in small animals such as rats.

Prediction of brain delivery of ofloxacin, a new quinolone, in the human from animal data

We attempted to predict the delivery of ofloxacin (OFLX), a new quinolone antibacterial agent (NQ), into cerebrospinal fluid (CSF) in the human based on the physiological properties and pharmacokinetic paramters of NQs in various animals. Physiological properties for evaluation of drug delivery into CSF such as volume and the bulk flow rate of CSF and weight of choroid plexus, were compared among the rat, rabbit, cat, dog, and human. Statistically significant correlations with power values of 0.82–0.89 in the linear regression were observed on log-log plots between brain weight and those properties of each species. Delivery of OFLX into CSF from blood was analyzed by “diffusion and flow model” with unidirectional efflux process from CSF to blood. The blood-CSF diffusion clearance and the efflux clearance of OFLX in the human were extrapolated from animal data based on the allometric correlations between brain weight and these parameters in the rat, rabbit, and dog. The apparent volume of distribution and the total body clearance of NQs in the human could also be predicted from animal data based on the classical Adolph-Dedrick approach. To simulate the CSF concentration-time profile of OFLX in the human by using these predicted parameters, it was necessary to consider both the lumbar CSF compartment and the ventricular CSF compartment. Both plasma and CSF concentration-time profiles of OFLX predicted from only animal experimental data were in good agreement with those observed clinically.

Delayed Elimination of Methotrexate Associated with Piperacillin Administration

triptyline toxicity. Because the patient had previously tolerated protriptyline alone, we propose that the toxicity was due to an elevated protriptyline concentration caused by fluoxetineand norfluoxetine-induced inhibition of CYP206 for five reasons. First, hallucinations were temporally related to the addition of protriptyline to a fluoxetine regimen, and did not recur after the discontinuation of protriptyline. Second, other causes of hallucinations appear unlikely; the patient had no history of psychotic symptoms or schizophrenia. Third, visual and olfactory hallucinations are more typical of an anticholinergic-induced psychosis than psychosis associated with depression or schizophrenia. Central anticholinergic toxicity can occur in the absence of peripheral symptoms. Fourth, she had tolerated protriptyline alone in the recent past. Fifth, the phenomenon of clinically significant decreased clearance of TCAs in the presence of fluoxetine sometimes resulting in TCA toxicity is well known.P It is caused by fluoxetineand norfluoxetine-induced inhibition of a major rate-limiting enzyme system ofTCA metabolism: hepatic CYP206.2.3 This phenomenon has been reported with several TCAs including imipramine, desipramine, nortriptyline, and clomipramine, but not, to our knowledge, with protriptyline. The chemical fate of protriptyline is similar to that of other TCAs. In humans, the main route of protriptyline metabolism is oxidation to form IQ-hydroxy and 10,II-dihydroxy derivatives that undergo conjugation with glucuronic acid.4.5 This similarity suggests a potential for a protriptyline-fluoxetine interaction. Although the CYP2D6 pathway for protriptyline is a reasonable speculation given that other TCAs have analogous pathways, it is conceivable that fluoxetine (and particularly norfluoxetine) might have inhibited the CYP3A4 enzymatic pathways, or both CYP2D6 and CYP3A4, to increase the concentrationand therefore the clinical effects of protriptyline. Another plausible explanation for this patients toxic delirium could be an idiosyncratic reaction to fluoxetine. Because the symptoms cleared when fluoxetine was discontinued, it is possible that protriptyline-induced inhibition of the CYP2D6 component of fluoxetines elimination led to increasedconcentrations and toxicity of fluoxetine. The drug of choice for anticholinergic delirium is physostigmine, but haloperidol was given to this patient because psychosis was the most prominent symptom of delirium. Although not used specifically to treat the underlying cause of anticholinergic delirium, generally haloperidol can be successfullyused for symptomatic treatment of psychosis in delirium. In the differentialdiagnosis, a psychotic disorder (without delirium) due to protriptylinetoxicity needs to be considered. In conclusion, this case suggests that protriptyline, like other TCAs, may have a potential for interaction with fluoxetine. It is the only lowclearance TCA: the mean elimination half-life is about 74 hours (range 53-91) and estimated first-pass metabolism is also low 00-25% of the oral dose).The issue that needs to be addressed is whether the low clearance of protriptyline enhances a propensity toward interaction with fluoxetine.~ 5. Ziegler VE, Biggs11, Wylie LT, CoryellWH, HaniflKM, HawfOJ,et al. Protriptyline kinetics. Clin Pharmacol Ther 1978;23:580-4.

Receptor occupancy theory-based analysis of antiemetic effects and standard doses of 5-HT3 receptor antagonists in cancer patients

PurposeThe aim of this study was to determine the usefulness of receptor occupancy theory-based analysis using pharmacokinetic and pharmacodynamic parameters for predicting the average receptor occupancy (ΦB) in humans of each of five 5-HT3 antagonists administered at standard doses.MethodsThe relationship between the ΦB value and the complete vomiting inhibition rate after a single intravenous administration of cisplatin (not less than 50xa0mg/m2) was analyzed.ResultsThe predicted ΦB values after intravenous administration and oral administration of 5-HT3 antagonists were more than 65% and 50%, respectively, suggesting that relatively high receptor occupancy is required to elicit sufficient antiemetic effects of 5-HT3 antagonists. Moreover, significant (P<0.05) linear relationships were found between ΦB values and complete vomiting inhibition rates of 5-HT3 antagonists in preventive cisplatin therapy, with correlation coefficients higher than 0.9, suggesting that the 5-HT3 receptor occupancy is an appropriate index of clinical efficacy of 5-HT3 antagonists, with higher receptor occupancy indicating more extensive antiemetic action.ConclusionThe receptor occupancy theory-based analysis of the antiemetic effect of a 5-HT3 receptor antagonist used in this study should be very useful for not only estimating a rational dosage regimen but also determining the standard dose of a new drug using experimental data obtained in a preclinical study.

Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats

AbstractPurpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed.nMethods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis.nResults. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model.nConclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.

Pharmacokinetics and pharmacodynamics of FK143, a nonsteroidal inhibitor of steroid 5α‐reductase, in healthy volunteers

The pharmacokinetics and pharmacodynamics of FK143, a new nonsteroidal inhibitor of steroid 5α‐reductase, were investigated in healthy volunteers, with use of plasma FK143 concentrations and serum dihydrotestosterone levels as an index for pharmacologic effects. The area under the plasma concentration‐time curve from zero to infinity [AUC(0‐∞)] and maximum plasma concentration [Cmax] were increased dose proportionally after oral administration (100 to 500 mg) while subjects were in the fed state. The AUC(0‐∞) and Cmax after 500 mg oral administration during fed conditions were significantly larger than those during the fasted state, suggesting an increase of the absorption of FK143. Dihydrotestosterone concentrations after a single administration of FK143 (100 to 500 mg) during fed conditions decreased to about 65% of predose values and thereafter slowly recovered to the same levels as predose values at 168 hours. A combined pharmacokinetic‐pharmacodynamic model was constructed with use of changes in dihydrotestosterone concentrations. The pharmacokinetic‐pharmacodynamic profiles of FK143 after repeated administration were predictable with use of the pharmacokinetic‐pharmacodynamic parameters obtained after a single administration of FK143.

Toxicodynamic analysis of cardiac effects induced by four cholinesterase inhibitors in rats.

The cardiac effect of edrophonium (2–20 μmol kg−1), pyridostigmine (0.5‐5 μmol kg−1), neostigmine (0.05‐0.5 μmol kg−1) and ambenonium (0.02‐0.3 μmol kg−1) was investigated after intravenous administration to rats.

Effect of renal or hepatic dysfunction on neurotoxic convulsion induced by ranitidine in mice.

We investigated the effect of acute renal and hepatic dysfunction on the neurotoxicity of ranitidine, a histamine H2 receptor antagonist. Experimental acute hepatic and renal dysfunction in mice were produced by i.p. injection of uranyl nitrate (UN) and carbon tetrachloride (CT), respectively. Ranitidine was then constantly infused into the tail vein until the onset of clonic convulsion. When compared to control mice, UN treated mice had a significantly shorter onset time to clonic convulsion, lower total dose and higher plasma concentration at initiation of clonic convulsion. In contrast, the convulsive threshold concentration in the brain of UN treated mice was not significantly different from that of control mice. In CT treated mice, all pharmacokinetic and pharmacodynamic data described above were not significantly different from those of the control mice. No significant difference in the brain/plasma concentration ratio was observed between both disease models and the corresponding control mice. Finally, the effect of UN and CT treatment on the convulsive potency after intracerebral (i.e.) administration of ranitidine was investigated in mice. Potentiation of the intrinsic neurotoxic sensitivity to ranitidine could not be demonstrated for mice with renal or hepatic dysfunction. From these findings, we conclude that renal dysfunction is a risk factor for ranitidine neurotoxicity, and this increased risk results from increase in the drug concentration in plasma and brain as a result of impaired renal excretion. No apparent effect of acute hepatic dysfunction was observed on both the pharmacokinetic and pharmacodynamic behavior of the drug.

Analysis of Antiplatelet Effect of Ticlopidine In Humans: Modeling Based on Irreversible Inhibition of Platelet Precursors in Bone Marrow

The relationship between plasma concentration of ticlopidine and its inhibitory effect on platelet aggregation in human was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model. The data of plasma concentration and inhibitory effect on platelet aggregation were taken from the literature. A two-compartment open model was fitted to plasma ticlopidine concentrations. Assuming that ticlopidine acts on platelet precursors in the bone marrow, the apparent reaction rate constant of ticlopidine and platelet precursors (K), apparent transformation rate constant of platelet precursors (kr) and apparent elimination rate constant of platelets (ke) were estimated. The estimated values ± S.D. were 1.01 ± 1.08 ml μg−1 hr−1for K, 0.265 ± 0.259 hr−1for krand 0.0747 ± 0.0112 hr−1for ke. The antiaggregation effects of ticlopidine on platelets after administration of 100, 200, and 300 mg (bid for 8 days) were simulated using the PD parameters of K, kr, and ke. While the antiaggregation effect reached steady state within 3–4 days without dose dependency of the interval, the maximum effect increased with dose. Furthermore, changing the elimination rate constant of ticlopidine from the central compartment in the model significantly changed the duration of inhibitory effect of ticlopidine on platelet aggregation. Therefore, the reported long duration of antiplatelet effect after discontinuation of ticlopidine, which is believed to be irreversible binding to the platelet, might have been partially caused by the delayed plasma elimination after a long therapy of ticlopidine. On the other hand, the mean life-span of platelets in the blood estimated by 1/keafter administration of ticlopidine was 14 hr, far below the life-span of platelets in the blood. For a more detailed analysis of the antiplatelet effect of ticlopidine, the possible contribution of reversible binding of the drug to glycoprotein IIb/IIIa should be considered in future PK/PD models.