Short-Chain Alkyl Esters of L-Dopa as Prodrugs for Rectal Absorption

The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable (>360 min) to hydrolysis in physiological buffer. In vitro enzymatic hydrolysis of the esters in plasma was species dependent, with the hydrolytic rate being faster in rat plasma (t _1/2 < 5 min) than dog plasma (t _1/2 = 68–181 min) or human plasma (t _1/2= 96–238 min). In vivo hydrolysis in dogs, as indicated by the L-dopa plasma profile following intravenous administration of the esters, was very rapid (high extravascular esterase activity). Significant L-dopa bioavailability was observed in rats following rectal administration of the methyl (46%), ethyl (14%), isopropyl (48%), butyl (100%), and 4-hydroxybutyl (13%) esters of L-dopa (rectal L-dopa absorption, <5%). In dogs, significant L-dopa bioavailability was also observed for the methyl (28%), isopropyl (30%), butyl (32%), and 4-hydroxybutyl (34%) esters of L-dopa in the presence of carbidopa. The data indicate that these highly water-soluble (>600 mg/ml) esters of L-dopa are potential candidates for controlled-release rectal delivery systems designed to provide more constant plasma L-dopa levels.     

Oral Absorption of D-Oligopeptides in Rats via the Paracellular Route

Purpose. This study was undertaken to examine the structural determinants of oral bioavailability in the rat of a set of oligopeptides comprising D-amino acids, which were taken to be absorbed paracellularly based on a pronounced sensitivity of permeability to electrical resistance in Caco-2 cell monolayers. Methods. The study series comprised eleven D-oligopeptides, designed not to be recognised by peptidases or transport proteins, and to have molecular weights between 222 and 406 daltons with different net electrical charges and composition of D-amino acids. All the peptides were [³H]-radiolabelled and analyzed by HPLC with radiometric detection. Bioavailability was estimated based on 24-hr urinary excretion of unchanged peptide after oral and intravenous administrations. Results. As expected, the series proved metabolically stable. Bioavailability was independent of oral dose when varied by a factor of 10,000, suggesting passive absorption. Whereas bioavailability decreased sharply from 30% to 1% with increasing molecular weight, net charge showed little, if any, effect on bioavailabilty. Conclusions. This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.     

The Effects of Carbidopa Dose and Time and Route of Administration on Systemic L-Dopa Levels in Rats

The effects of carbidopa dose and time and route of administration on systemic plasma levels of parenterally and nonparenterally administered L-dopa were examined in rats. Intravenous coadministration of L-dopa + carbidopa resulted in significant (P < 0.05) carbidopa-dependent increases in both the area under the plasma L-dopa concentration versus time profile (AUC; +27%) and the plasma L-dopa half-life ( . Simultaneous duodenal or rectal carbidopa administration did not alter the L-dopa i.v. pharmacokinetic profile. Carbidopa pretreatment significantly increased the i.v. L-dopa AUC ( + 38 and +82% for i.v. and duodenal pretreatments, respectively) compared to simultaneous administration. Both i.v. and duodenal carbidopa increased duodenal L-dopa AUC to a similar extent ( + 282 and +239% for i.v. and duodenal administration, respectively). Rectal studies indicated poor absorption of both L-dopa and carbidopa, with no demonstrable effect on plasma L-dopa. The results indicate that the timing and route of carbidopa and L-dopa administration are important in determining the extent of i.v. or duodenal L-dopa systemic availability. The rat model affords results similar to those reported in human studies and may be useful for more extensive evaluation of L-dopa and carbidopa interactions.     

Regional Rectal Perfusion: A New in Vivo Approach to Study Rectal Drug Absorption in Man

Background: In vivo permeability measurements of drugs in the colonic/rectal region in humans are difficult. A new instrument for the perfusion of a defined and closed segment in the colon/rectum was developed. The objective of this study was to evaluate its use for studying drug absorption mechanisms in the human rectum and to investigate the effect of transmucosal water absorption on drug permeability. Six healthy subjects participated at 2 separate occasions by using a modified system for segmental rectal perfusion. The system consisted of a multichannel tube with inflatable balloons and was endoscopically introduced into the rectum. The technique was considered acceptable by the following criteria; (a) high and reproducible recovery of PEG 4000, (b) stable residence time of the solution within the test segment, (c) flux of electrolytes that agrees with previous reports, (d) mass-balance absorption of antipyrine across the rectal barrier, (e) and good acceptability to the subjects. The permeability of antipyrine in the rectal region was increased by inducing net water absorption. D-glucose was not absorbed during any study periods. The present technique is valuable for studying drug absorption from the human rectum.     

Enhanced Bioavailability of 6-Mercaptopurine After Rectal Administration in Rats

Pharmaceutical Research -     

The Rate and Extent of Oral Bioavailability versus the Rate and Extent of Oral Absorption: Clarification and Recommendation of Terminology

In the literature, the meanings of the terms oral absorption and oral bioavailability of drugs vary greatly. Absorption has been considered to take place at the mucosal membrane of the gastrointestinal (GI) tract. It has also been defined as the process from the site of drug administration to the site of measurement. In the latter definition, the extent of oral absorption depends on the extent of first-pass elimination in the gut wall and liver even though a drug may be completely absorbed from the GI tract. Moreover, these two terms have also been used interchangeably. Inconsistency in the definition of these two terms has led to varying interpretations of these terms among students, researchers and laymen, and such an inconsistency seems undesirable. Apparently because of these inconsistencies, improper correlations between the Caco-2 permeability or intestinal permeability and the oral bioavailability of drugs subject to extensive first-pass effect may have occurred. It is suggested that absorption be defined as movement of drug across the outer mucosal membranes of the GI tract, while bioavailability be defined as availability of drug to the general circulation or site of pharmacological actions. Since transit times (this may range from about 1 min to several hours) across enterocytes, liver, lungs, and the peripheral venous sampling tissue are virtually unknown for all drugs, this factor alone would favor the use of oral bioavailability rate rather than oral absorption rate in all routine studies.     

Oral Absorption of FK506 in Rats

The oral absorption of FK506 in solid dispersion formulation was studied in rats. The obtained area under the concentration versus time curve (AUC) increased in a nonlinear fashion with a small dose-dependent increase in the peak blood concentrations (C _max). The peak concentration time (T _max) was observed within 30 min after administration in all dosing groups (1–10 mg/kg) with or without feeding, whereas the oral absorption of FK506 was reduced to about 50% by gavage at a dose of 1 mg/kg. Participation of first-pass elimination was suggested by comparing the blood levels after infusion via the portal vein with those after infusion via the femoral vein. Further, in an in vitro stability study and an in situ loop absorption study, FK506 was fairly stable in the gastrointestinal juice and was absorbed predominantly from the upper part of the small intestine.     

积雪草酸脂质纳米粒的大鼠口服吸收研究

目的 考察大鼠口服积雪草酸纳米结构脂质载体(asiatic acid loaded nanostructured lipid carriers,AA-NLC)的口服吸收情况。方法 建立清醒大鼠胆汁引流模型,按50 mg·kg^-1的剂量灌胃给予AA-NLC和积雪草酸(asiatic acid,AA)原料(对照组),采用柱前衍生化HPLC检测胆汁药物浓度,考察AA纳米粒的吸收状况。结果 大鼠口服AA-NLC后,药物排泄峰值C_max是对照组的1.7倍,达峰时间T_max显著慢于对照组(P<0.05),AA-NLC的消除慢于对照,其消除半衰期T_1/2是对照组的2.7倍,与纳米粒吸收有关的药时曲线下面积AUC_{0-24 h}与对照组相比提高了150%。结论 新建立的口服吸收评价方法,初步评价AA-NLC大鼠灌胃后的吸收特性,AA制备成纳米结构脂质载体后可增加口服生物利用度。     

Soft Drugs 18. Oral and Rectal Delivery of Loteprednol Etabonate,a Novel Soft Corticosteroid,in Rats—for Safer Treatment of Gastrointestinal Inflammation

Purpose. As a safe anti-inflammatory corticosteroid, the utility of loteprednol etabonate (LE) for the treatment of gastrointestinal inflammation, via oral and rectal administration, was investigated in rats. Methods. In vivo, LE solution and suspension were orally administered (20 mg/kg), and various LE preparations (solution, suspension & suppository) were applied in rectal loops (0.2 mg per loop). In vitro, various GI tissues were used to study the stability and partition of LE. Results. After oral administration of LE solution, LE reached the upper GI tract effectively, but not the colon, due to absorption and/or decomposition. In suspension, LE reached most of the GI tract (except rectum) in 8 hr and showed little absorption. After rectal applications, LE remained intact in the rectal loop for more than five hours with a slow rate of disappearance, however, LE distributed in the rectal membrane to some extent. The concentrations of LE and its inactive metabolites in plasma after both oral and rectal administrations were lower than the detection limit (0.1 µg/ml) at anytime during the experiments. In vitro, LE in solution was stable in stomach, but not in cecum, due to the hydrolysis by the cecal resident micro flora. In solution, LE distributed into the mucosal membranes efficiently (about 2.5 ~ 4.0 µg/g tissue). Conclusions. The results suggest that LE can be orally or rectally delivered in the GI tract for the topical treatment of the inflammatory bowel disease.     

Decanoic Acid Induced Enhancement of Rectal Absorption of Hydrophilic Compounds in Rats

The enhancing effect of decanoic acid (CIO) on the rectal absorption of phenolsulfonphtalein (PSP) was analyzed with a pharmacokinetic model. The transfer index of PSP from the rectal lumen to the epithelial layer in the presence of C10 was proportional to the product of the C10 disappearance rate from the rectal lumen and its calcium ion sequestration capacity. The enhancement of rectal PSP absorption by different doses of C10 was also predictable by using a permeability index, Pa, of PSP, which was defined as a proportionality constant relating transfer index and the product value described above. The Pa values of various hydrophilic compounds with different molecular weights were also estimated from their rectal bioavailability in the presence of C10. A linear relationship was observed between Pa values and reciprocal values of the square root of individual molecular weight. These findings suggest that the Pa index is related to the permeants diffusion coefficient through paracellular aqueous openings formed by C10.     

Absorption of Diazepam in Man Following Rectal and Parenteral Administration

Abstract Serum concentrations of diazepam and N-desmethyldiazepam were measured in six adult patients following administration of 10 mg diazepam in solution by the rectal, intravenous, and intramuscular routes. Maximum serum concentrations of 121-200 ng/ml were recorded from 10 to 20 min. after the rectal instillation, whereas following intramuscular injection the levels rose slowly and irregularly, reaching a maximum (62-186 ng/ml) in 1 to 24 hours. The bioavailability of diazepam given by rectal instillation was found to be 50±17 per cent (mean±S. D.) as compared with the intravenous administration. The possible reasons for the low bioavailability are discussed. It is concluded that administration by rectal tube provides a useful alternative to the tablets (and intramuscular injections) when a rapid onset of effect of the drug is wanted, and when intravenous administration is not applicable or practical.     

Influence of Indomethacin Amphoteric Gel on Gastric Ulcerogenicity and Absorption of Indomethacin in Rats

Indomethacin is a potent and efficacious antiinflammatory agent. However, a limiting side effect is its ability to cause gastric ulceration. This study was designed to investigate the effects of an amphoteric gel on the gastric ulcerogenicity and pharmacokinetics of indomethacin. Oral administration (5 mg/kg) in a suspension and a gel formulation were compared to an intravenous (iv) formulation of indomethacin in rats. The iv formulation administered to rats produced large severe ulcers in some rats but not in others. In contrast, the oral suspension produced small ulcers in all rats. The difference in toxicities is attributed to a centrally mediated action as a result of high plasma levels of indomethacin following iv administration, compared to locally mediated action with the suspension, resulting from local high concentrations of indomethacin on the apical epithelial surface because of the presence of indomethacin crystals. Oral administration of the gel formulation did not result in any gastric ulceration and improved the bioavailability of indomethacin to 115.5%, compared with 68.2% for the suspension. The reduced gastrointestinal toxicity of indomethacin in the gel was attributed to the gel's ability to dissolve indomethacin, preventing the localized high concentration observed with the suspension and possibly providing a gastric protectant phospholipid. The gel formulation doubled the oral bioavailability and the t _max of indomethacin compared to the suspension but did not affect the half-life. The results indicate that the local irritant effect of indomethacin, in rats, can be reduced by appropriate formulation design and suggest that the ulcerogenicity index for indomethacin can be improved by the use of an amphoteric gel formulation.     

Comparison of Oral Absorption and Bioavailability of Drugs Between Monkey and Human

Purpose. To compare the oral absorption and bioavailability of numerous drugs with a wide variety of physicochemical and pharmacological properties between humans and monkeys and to explore potential reasons for the findings. Methods. Data for fraction of dose absorbed (F _a) and oral absolute bioavailability (F) were obtained by an extensive Medline database search. Inclusion and exclusion criteria were the same as those reported in our previous studies. A total of 43 and 35 drugs were selected for F _a and F comparison, respectively. The time to reach peak concentration (t _max), total clearance, and nonrenal clearance were evaluated for 15, 28, and 13 drugs, respectively. Results. F _a values in monkeys were similar or identical to those in humans. Additionally, similar t _max values were seen in monkeys and humans at comparable doses, thus indicating comparable absorption kinetics between the two species. Conversely, F values in monkeys were generally lower with coumarin being a marked exception. Both total and nonrenal clearances were evaluated and found to be generally greater in monkeys, supporting a generally higher first-pass metabolism and lower F in this species. This was also supported by published data suggesting greater in vitro hepatic drug metabolism for monkeys as compared to humans. Conclusions. Monkeys appear to be a good predictor of F _a in humans. However, a generally lower F makes monkeys a potentially poor predictor of human F. Higher reported metabolic clearances and hepatic enzyme activities in monkeys may account for this observation.     

Nitric Oxide Donors Enhance Rectal Absorption of Macromolecules in Rabbits

Purpose. The objective of this investigation is to evaluate the potential of nitric oxide (NO) donors as a new class of absorption enhancers which may act on intestinal epithelial cells through epithelial actions of the chemical mediator, NO. Methods. Suppositories containing NO donors and insulin were administered into the rabbit rectum. After administration of the suppository, blood samples were collected from the auricular vein. The plasma insulin and glucose concentrations were determined. Results. The NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP, 4 mg) induced a significant increase in the rate of insulin absorption from the rectum. Administration of a suppository containing SNAP without insulin affected neither the plasma insulin nor the plasma glucose concentration. Other NO donors, NOR1 and NOR4, also induced increases in the insulin absorption. The absorption enhancement effect of SNAP was inhibited by coadministration of the NO scavenger carboxy-PTIO. SNAP also enhanced FITC-dextran (MW 4,000) absorption. Little cytotoxicity of SNAP (3.0 mg/ml) as assessed in terms of the rate of lactate dehydrogenase (LDH) release from Caco-2 cells was detected for 2 h of incubation. Conclusions. These findings suggest that NO enhanced macromolecular absorption from the rectum without mucosal cell damage, and that NO donors can act as potent absorption enhancers.     

Theoretical Considerations on Two Equations for Estimating the Extent of Absorption After Oral Administration of Drugs

Purpose. The amount of drug absorbed into portal blood after oral dosing (D_p.o,g) has been estimated using Ficks principle (Q-method), i.e., D_p.o,g = Q_h · (AUC_p.o,g – AUC_p.o,c), where Q_h is the portal blood flow rate, and AUC_p.o,g and AUC_p.o,c are the areas under the concentration-time curves of portal vein and systemic blood after oral dosing, respectively. However, this method may underestimate D_p.o,g, when the drug is subject to systemic intestinal elimination. An alternate equation (CL-method; D_p.o,g = CL_S · AUC_p.o,g) is described using a simple pharmacokinetic model, to estimate D_p.o,g in the presence of systemic intestinal elimination, where CL_S is systemic clearance. Methods. The model is composed of central, intestine and liver compartments, assuming that drug is eliminated by intestinal and/or hepatic pathways only. A comparison of both methods for estimating D_p.o,g was made using computer-simulation or experimental data of phenacetin from the literature. Results. The simulation study demonstrated that the Q-method underestimated D_p.o,g in the presence of significant intrinsic intestinal clearance, compared to the CL-method,. The similar results were observed using the experimental data of phenacetin. Conclusions. The CL-method can provide a better estimate of D_p.o,g, while the Q-method may underestimate D_p.o,g, when there is significant systemic intestinal elimination of drugs after oral administration. In addition, useful information for understanding the relationship between the extent of absorption and the first-pass effect by intestine and/or liver after oral dosing of drugs can be obtained from the present approach.     

Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats

Purpose  PEPT1 mediates the intestinal absorption of many drugs, but its contribution to oral absorption of drugs is still controversial. The objective of this study is to quantitatively evaluate the contribution of PEPT1 to oral absorption of cephalexin, a typical substrate for PEPT1, in rats. Materials and Methods  The absorbability of cephalexin via PEPT1 or passive diffusion was assessed in five intestinal segments by utilizing glycyl-proline as a competitive inhibitor by in-situ closed loop method. Absorption kinetics of cephalexin after oral administration was predicted by GI-Transit-Absorption model. Results  Absorbability of cephalexin was segment-dependent, and concentration-dependent in all the segments except for the lower ileum. Intrinsic absorption rate constant via PEPT1 ranged from 0.64 to 4.07 h⁻¹. The absorption rate constants via passive diffusion ranged from 0.78 to 1.24 h⁻¹. Plasma concentration–time profile of cephalexin was successfully predicted and the substantial contribution of PEPT1 to the oral absorption was calculated to be from 46% to 60% of total absorption. Simulation study indicated that 83% bioavailability would be expected for cephalexin even though PEPT1 does not function. Conclusions  PEPT1 substantially contributes to oral absorption of cephalexin, around a half of total absorption. However, the function of PEPT1 can be compensated by passive diffusion for cephalexin.     

Disposition and Oral Bioavailability in Rats of an Antiviral and Antitumor Amino Acid Phosphoramidate Prodrug of AZT-Monophosphate

Purpose. The purpose of this study was to characterize the in vivo disposition of 3-azido-2-deoxythymidine-5-methylamino-L-trypto- phanylphosphoramidate (NMe-Trp-AZT), a potential pronucleotide of 3-azido-2-deoxythymidine monophosphate (AZT-MP). Methods. The in vitro metabolic stability of NMe-Trp-AZT was evaluated in a wide variety of tissue homogenates. NMe-Trp-AZT was administered orally (n = 3) to female Sprague-Dawley rats. Its biliary excretion and intestinal permeability were also studied. Results. Renal excretion of unchanged prodrug (16.4 ± 5.6% of the total dose administered intravenously), its conversion to AZT (12.1 ± 5.4% of total dose administered intravenously), and its biliary excretion (54.3 ± 4.9% of the total dose up to 4 h after intravenous administration) accounted for most of the elimination of NMe-Trp-AZT. Significant amounts of AZT were found in both plasma and urine after oral administration of the prodrug. The prodrug itself was not permeable through the small intestinal wall but was slowly converted to AZT-MP in gastric fluids at low pH. Conclusions. The NMe-Trp-AZT prodrug itself was not orally bioavailable because of poor intestinal permeability; however, AZT was readily available in the systemic circulation after the oral administration of the prodrug. Modification of the phosphoramidate to promote intestinal uptake should lead to enhanced oral bioavailability of this and other nucleoside phosphoramidate monoesters.     

Rectal absorption of flecainide acetate

Summary The rectal absorption of flecainide from an aqueous solution, a fatty suppository and a polyethyleneglycol suppository was studied in one patient with supraventricular tachycardia (Wolff-Parkinson-White syndrome) refractory for oral anti-arrhythmic treatment.Rectal absorption was found to be fast (t_1/2abs=1 h) and complete when flecainide was administered as a solution (relative bioavailability 100%).Flecainide was poorly absorbed from a fatty suppository. The polyethyleneglycol suppository gave absorption with a relative bioavailability of 80% and t_{1/2 abs}=1.2 h.     

葛根素固体分散体的制备及大鼠体内生物利用度研究

本文采用新型的固体分散体技术,将葛根素,磷脂与PVP制成固体分散体,对其理化性质进行研究,考察固体分散体在大鼠体内的药一时曲线,计算其在大鼠体内的药动学参数,并与葛根素原料比较,研究固体分散体的相对生物利用度。结果表明以磷脂和PVP为载体制备的固体分散体（药物-磷脂-PVP,2：4：1）的表观油水分配系数最好,固体分散体相对生物利用度较纯葛根素提高了2．53倍。