Current Drug Metabolism - Volume 8, Issue 2, 2007

Ophthalmic drugs are delivered to ocular tissues predominantly via relatively simple formulations, such as topically dosed water-soluble drug solutions and water-insoluble drug suspensions in ointments. An ideal topical drug delivery system should possess certain desirable properties, such as good corneal and conjunctival penetration, prolonged precorneal residence time, easy instillation, non-irritative and comfortable to minimize lachrymation and reflex blinking, and appropriate rheological properties. In general, ocular efficacy is closely related to ocular drug bioavailability, which may be enhanced by increasing corneal drug penetration and prolonging precorneal drug residence time. To improve ocular bioavailability of topically dosed ophthalmic drugs, a variety of ocular drug delivery systems, such as hydrogels, microparticles, nanoparticles, microemulsions, liposomes and collagen shields, have been designed and investigated. These newer systems may, to some extent, control drug release and maintain therapeutic levels in ocular tissues over a prolonged period of time. This review focuses on the in vitro, ex vivo and in vivo studies of ophthalmic drugs formulated in nanoparticles published over the past two decades. The progress and development issues relating to ocular disposition, pharmacokinetics, efficacy and safety of the nanoparticle-formulated ophthalmic drugs are specifically addressed. Information and discussions summarized in this review are helpful for pharmaceutical scientists to develop better ophthalmic therapeutics.

Patients vary considerably in their response to drug therapy. A drug that proves to be pharmacologically effective in some patients at a given dose may be ineffective or even toxic in others. The interindividual variability in drug response represents a major challenge in drug therapy, particularly for drugs with narrow therapeutic index. The intensity and duration of a drug action are determined not only by pharmacokinetic processes, but also by pharmacodynamic processes. Therefore, the variability in drug response is a result of the variability in either pharmacokinetic or pharmacodynamic processes, or a combination of both. The purpose of this paper is to review the sources that contribute to pharmacokinetic and pharmacodynamic variability. Although the main focus will be on the genetic variability, the impact of environmental factors on drug response will also be discussed. Finally, the application and limitation of the concept of personalized medicine will be briefly discussed.

Quinones represent a very important class of compounds found in nature and for the chemically synthesized drugs. The present study was designed to elucidate the intestinal first pass metabolic pathways in vivo and in vitro, of tanshinone IIA (TS), a derivative of phenanthrene-quinone isolated from Salvia miltiorrhiza. Five metabolites, proposed to be TS catechol glucuronides (two position isomers), dehydrotanshinone IIA and its two catechol glucuronides, were identified from the rat intestinal homogenates after oral administration of TS. TS metabolism was further conducted in the subcellular system including cytosol, microsomes, mitochondrial and S9 under both phase I and phase II metabolic conditions. TS underwent negligible metabolism in all of the subcellular systems under phase I metabolic condition using NADPH as the cofactor. However, significant and substantial metabolic elimination of TS was observed in the cytosol and S9 fractions, while not in the microsomes fractions, when both NADPH and UDPGA were added. Two TS catechol glucuronides were identified from such an in vitro metabolic medium. Dicoumarol, a specific inhibitor of the NAD(P)H dependent quinone oxidoreductase (NQO1), significantly inhibited the metabolic elimination of TS in a noncompetitive way, suggesting that NQO1 was responsible for the quinone reduction of TS to form the catechol intermediate. The catechol intermediate failed to be detected directly was proved to be highly unstable and autoxidized back to TS accompanied with hydrogen peroxide generation. Dicoumarol exhibited a significant inhibitory effect on the hydrogen peroxide generation, further supporting that the reduction of TS was catalyzed by NQO1. The absolute bioavailability of TS was significantly enhanced by oral dicoumarol pretreatment. In conclusion, a novel intestinal metabolic pathway for quinones, NQO1 mediated reduction and subsequent glucuronidation, was determined using TS as a model compound. This study should be helpful for the general understanding of quinones absorption and intestinal first pass metabolism.

The disposition and diffusion knowledge of intravitreally injected macromolecule drugs through retina in pathological condition is crucial but the related studies are absent. Retinal edema is a common pathological change of fundus diseases and retinal vein occlusion (RVO) pig model were established to emulate it. FITC-dextrans of various molecular weights were dissolved in RPMI-1640 solutions and the rate of transretinal diffusion was determined with a spectrophotometer. Theoretical maximum size of molecule (MSM) was calculated by extrapolating the trend-linear relationship with the diffusion rate. In separate experiments to determine the sites of barrier to diffusion, FITC-dextrans were applied to either the inner or outer retinal surface, processed as frozen sections, and viewed with a fluorescence microscope. Paired-Samples T test was used to compared the diffusion rate of dextrans of the both eyes of one pig. The MSM in RVO tissues and normal tissue was 6.5+0.39nm and 6.18+0.54nm respectively (t=4.143, P=0.0001). FITC-dextrans applying to inner retinal surface, 4.4 kDa dextran were largely arrested at inner nuclear layer (INL). The INL of the 19.6∼71.2 kDa dextran diffusion retina section became dark and the nerve fiber layer (NFL) and inner plexiform layer got brighter. As for 150 kDa dextran, the NFL was bright and the other layers were dark. FITC-dextrans applying to outer retinal surface, most dextrans were blocked before outer nuclear layer (ONL). In summary, ONL and INL may act as bottle-neck barriers to diffusion of macromolecules. Compared with normal neuroretina, the MSM of fresh edema retina after RVO increased limitedly.

Irinotecan (CPT-11) is an important anticancer drug in management of advanced colon cancer. A marked protective effect on CPT-11-induced blood and gastrointestinal toxicity is obtained by combination of St. John’s wort (SJW) in recent clinical and rat studies. However, the mechanism is unclear. This study aimed to explore the effects of SJW on the pharmacokinetics of CPT-11 and its major metabolites (SN-38 and SN-38 glucuronide) in rats and the underlying mechanisms using several in vitro models. Short-term (3 days) and long-term (14 days) pretreatment with SJW were conducted in rats to examine the effects of co-administered SJW on the plasma pharmacokinetics of CPT-11, SN-38 and SN- 38 glucuronide. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were utilized to study the effects of aqueous and ethanolic extracts (AE and EE) and major active components (hyperforin, hypericin and quercetin) of SJW on CPT-11 and SN-38 metabolism and intracellular accumulation. Co-administered SJW for consecutive 14 days significantly decreased the initial plasma concentration (C0) of CPT-11, the area under the concentration-time curve (AUC0-10hr) and maximum plasma concentration (Cmax) of SN-38. The ethanolic extracts (EE) of SJW at 5 μ g/ml significantly decreased SN-38 glucuronidation by 45% (P < 0.05) in rat hepatic microsomes. Pre-incubation of aqueous SJW extracts (AE) at 10 g/ml, SJW EE at 5 μg/ml, and quercetin at 10μ M significantly increased the glucuronidation of SN-38 in H4- II-E cells. A 2-hr pre-incubation of quercetin (100μ M) significantly increased the intracellular accumulation of CPT-11 (P < 0.05). However, pre-incubation of hypericin (20 nM and 200 nM) and hyperforin (1μ M) significantly decreased the intracellular accumulation of CPT-11. In addition, pre-incubation of hypericin, SJW EE and quercetin significantly increased the intracellular accumulation of SN-38. Aqueous and ethanolic SJW extracts and its major active components did not alter the plasma protein binding of CPT-11 and SN-38. These results indicated that the aqueous and ethanolic extracts of SJW and its major active components could markedly alter glucuronidation of SN-38 and intracellular accumulation of CPT-11 and SN-38, which probably provides partial explanation for the altered plasma pharmacokinetics of CPT-11 and SN-38 and the antagonizing effects on the toxicities of CPT-11. Further studies are needed to explore the role of both pharmacokinetic and pharmacodynamic components in the protective effect of SJW against the toxicities of CPT-11.

Sanguinarine, a quaternary benzo[c]phenanthridine alkaloid, exhibits antimicrobial and anti-inflammatory activities and for this reason it is used in dental hygiene products and feed additives. Its metabolism and disposition is the subject of constant scientific discourse. In this paper we summarize current knowledge on sanguinarine metabolism. We show in particular that: (i) Sanguinarine is not transformed to 3,4-benzacridine and that the literature reporting this compound as a metabolite of sanguinarine is based on artifacts and misinterpretations that in course of time have created a dogma; (ii) Sanguinarine is converted to dihydrosanguinarine in vivo, the conversion being tentatively a detoxication pathway; (iii) Aryl hydrocarbon receptor metabolic signaling pathways modulate sanguinarine biological activity.

Carbon monoxide (CO) is an endogenous gaseous messenger, which regulates numerous physiological functions in a wide variety of tissues. Using extracellular microelectrode recording from frog neuro-muscular preparation the mechanisms of exogenous and endogenous CO action on evoked quantal acetyl-choline (Ach) release were studied. It was shown that CO application increases Ach-release in dose-dependent manner without changes in pre-synaptic Na+ and K+ currents. The effect of exogenous CO on Ach-release was decreased by prior application of guanylate cyclase inhibitor ODQ and prevented by application of a cyclic guanylate monophospate (cGMP) analog 8Br-cGMP. Pre-treatment of the preparation with adenylate cyclase inhibitor MDL-12330A has completely abolished the effect of CO, whereas elevation of intracellular level of cyclic adenosine monophospate (cAMP) mimicked and eliminated CO action. Application of cGMP-activated phosphodiestherase-2 inhibitor EHNA did not prevent CO action, whereas inhibition of cGMP-inhibited phosphodiestherase-3 by quazinone has partially blocked the effect of CO. Utilizing immuno-histochemical methods COproducing enzyme heme-oxygenase-2 (HO-2) was shown to be expressed in skeletal muscle fibers, mostly in subsarcolemmal region, karyolemma and sarcoplasmic reticulum. Zn-protoporphirin-IX, the selective HO-2 blocker, has depressed Ach-release, suggesting the tonic activating effect of endogenous CO on pre-synaptic function. These results suggest that facilitatory effect of CO on Ach-release is mediated by elevation of intracellular cAMP level due to activation of adenylate cyclase and decrease of cAMP breakdown. As such, endogenous skeletal muscle-derived CO mediates tonic retrograde up-regulation of neuro-transmitter release at the frog neuro-muscular junction.

CYP3A4 is the most abundantly expressed drug-metabolizing P450 enzyme in human liver and contributes to the metabolism of a large number of drugs in use today. CYP3A4 is constitutively expressed in adult hepatocytes but it can also be transcriptionally induced by a variety of structurally diverse xenochemicals. CYP3A4 strongly contributes to the important variability in the therapeutic and toxic effects of drugs owing to the major role it plays in xenobiotic metabolism and the large intra- and inter-individual variability to which it is subjected. The functional examination of up to 13 kb of the CYP3A4 5'-flanking region has revealed that the regulation of this gene is a complex issue, with numerous transcription factors interacting with multiple promoter/enhancer elements. This also suggests that a high degree of human variability in the hepatic CYP3A4 expression could result from regulatory polymorphisms. Several transcription factors and nuclear receptors contribute to the hepatic-specific expression of CYP3A4, including: C/EBPγ , C/EBPβ , HNF4γ , HNF3γ , CAR and PXR. The induction phenomenon and the down-regulation of CYP3A4 in pathophysiological conditions, such as inflammatory situations, are key processes involved in the toxic vs. therapeutic effects of many drugs. Since CYP3A4 variation may affect the efficacy and toxicity of new drugs, development of reliable hepatic models for the assessment and prediction of the role of CYP3A4 in drug metabolism are important for drug development. Cultured human hepatocytes are the closest model to the human liver as far as CYP3A4 regulation and induction are concerned. However, other hepatic models should be considered in drug development for screening purposes owing to the limited availability of human hepatocytes.