Relationship between genetic polymorphisms of drug efflux transporter MDR1 (ABCB1) and response to losartan in hypertension patients.

OBJECTIVE: Losartan is a selective angiotensin II receptor type 1 blocker and a substrate of drug efflux transporter MDR1 (ABCB1). MDR1 shows inter-individual variations due to genetic polymorphisms. C3435T, G2677T and C1236T polymorphic alleles of the MDR1 gene encoding the transporter have been shown to alter the transport, bioavailability and efficacy of certain drugs. The purpose of this study was to investigate the relationship between genetic polymorphisms of MDR1 (C3435T, G2677T/A and C1236T) and response to the treatment in newly diagnosed hypertensive patients being treated with losartan. PATIENTS AND METHODS: A total of 74 newly diagnosed hypertension patients were included in the study. Genotyping was performed using PCR-RFLP. Systolic and diastolic mean blood pressure changes of the patients were expressed as a percentage (± SD). Blood pressure values prior to initiation of the treatment and subsequent measurements 6 weeks after starting the treatment were compared. RESULTS: Regarding the C3435T polymorphism, a mean decrease of systolic blood pressure in individuals with CT or TT genotype (n= 55; 11.6% ± 9.7 mmHg) was significantly higher compared with that of the CC genotype (n = 19; 6.7% ± 9.6 mmHg, p = 0.03). No significant systolic blood pressure changes observed in G2677T/A and C1236T genotypes (p = 0.13 and 0.07, respectively). There was not any significant difference in diastolic blood pressure changes between pre- and post-treatment for any of the genotypes with C3435T, G2677T/A, or C1236T variations. CONCLUSIONS: This study revealed that hypotensive response to losartan was significantly affected by the C3435T genetic polymorphism of MDR1 and hypertensive patients with MDR1 3435T allele may present a better response to losartan treatment.

Is a routine preoperative rectosigmoidoscopy necessary in patients with bilateral inguinal hernia?

OBJECTIVES: The purpose of this prospective study was to evaluate the association between bilateral inguinal hernias and colorectal cancers. PURPOSE: Inguinal hernias are one of the most common subjects in surgical practice and have been known to be associated with some other pathologies since 1831. Although there are some series in literature reporting the association of colorectal cancers with inguinal hernias, it is still controversial to perform colorectal diagnostic tools in hernia patients. Colorectal cancers are particularly accused to be in association with synchronous bilateral hernias as they increase the intra-abdominal pressure. METHODS: Rectosigmoidoscopy was performed in 110 consecutive bilateral hernia patients and the results were recorded prospectively. Patients having colorectal diseases were excluded. RESULTS: There were no pathologies in 87 (%79,1) rectosigmoidoscopies, while benign pathologies (hemorrhoids, polyps and diverticulitis) were diagnosed in 23 (%20,9). CONCLUSIONS: It has not been proved yet that colorectal cancers increase the incidence of bilateral inguinal hernias. The incidence of benign pathologies in our series was similar to that of same age population without hernia. As a conclusion of this study we believe that rectosigmoidoscopy is not necessary for synchronous bilateral hernias unless the patient has any complaints or risk factors. Colorectal screening tools are performed when the clinical findings or the story of the patient support colorectal cancers) (Tab. 1, Ref. 25).

Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients.

Cyclophosphamide (CPA) and adriamycin (ADR) are widely used drugs for cancer chemotherapy. It has been reported that CPA and ADR singly or in combination could alter activities of a variety of drug-metabolizing enzymes in animals via multiple mechanisms. However, the effects of CPA/ADR on drug metabolism are largely unknown in human beings. Losartan metabolism has been suggested as a marker for determination of CYP2C9 activity. Caffeine is a commonly used probe to assess the metabolic activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO). The present study was designed to analyze the effects of CPA/ADR on these drug-metabolizing enzymes by using losartan and caffeine as probe drugs. A single oral dose of 25 mg losartan and a cup of instant coffee was given to 15 breast cancer patients on three occasions (before, and 2-4 h and 3 weeks after the adjuvant CPA/ADR chemotherapy [600 mg CPA/m2/day, 60 mg ADR/m2/day]). Losartan, caffeine and their metabolites were analyzed by using high-pressure liquid chromatography. When compared with baseline, CYP1A2 activity was increased by 20% and CYP2C9 activity was decreased by 315% 3 weeks after the administration of CPA/ADR chemotherapy (p = 0.05). The chemotherapy did not change the activities of CYP2A6, NAT2 or XO. CPA/ADR treatment caused a differential effect on drug-metabolizing enzyme activities, and this may contribute to predicting the efficacy and toxicity of chemotherapeutics, as well as understanding the drug-drug interactions.

Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients.

Tamoxifen has been reported to potentiate the anticoagulant effect of warfarin and also to increase the plasma level of phenytoin, which are mainly metabolized by CYP2C9. The aim of this study was to determine the influence of tamoxifen on CYP2C9 activity in vivo in humans. Thirteen breast cancer patients who would start tamoxifen following cytotoxic chemotherapy were enrolled in the study. A single oral dose of 25 mg losartan was given to the patients 2 days before and 2 weeks after starting tamoxifen therapy. Losartan and E3174 in 8-hour urine samples were measured by HPLC. Tamoxifen significantly increased the average urinary losartan/E3174 ratio from 0.73 (CI 95% = 0.15 - 2.30) to 1.66 (CI 95% = 0.68 - 5.20), after 2 weeks of treatment (p = 0.002). Tamoxifen inhibited CYP2C9 activity in breast cancer patients within two weeks of its administration. The inhibition of CYP2C9 activity may be a possible explanation for the drug-drug interaction of tamoxifen with CYP2C9 substrates.

Variant alleles and genotypes of alcohol dehydrogenase 3 in a Turkish population.

Alcohol dehydrogenase (ADH) is a genetically polymorphic dimeric enzyme that is responsible for the metabolism of alcohol. ADH3 gene encodes for the gamma subunit of dimeric ADH and has an important role in the function of the enzyme. The aim of this study was to determine the frequencies of ADH3 alleles and genotypes in a healthy Turkish population sample. Genotypic assay was carried out in 102 unrelated volunteers. DNA samples were genotyped for the ADH3*2 allele. The ADH3*1 and ADH3*2 allele frequencies were determined as 0.66 (95% confidence interval [CI] = 0.57-0.75) and 0.34 (95% CI = 0.25-0.43), respectively. The genotype frequencies of ADH3*1/*1, *1/*2, and *2/*2 were 39% (95% CI = 30-49), 54% (95% CI = 44-64), and 7% (95% CI = 2-12), respectively. According to our results, the frequencies of variant ADH3 alleles and genotypes are similar to that in the other Caucasian populations.

Ketobemidone is a substrate for cytochrome P4502C9 and 3A4, but not for P-glycoprotein.

The role of the major drug-metabolizing cytochrome P450 (CYP) enzymes as well as P-glycoprotein (PGP) was investigated in the disposition of ketobemidone in vitro. Formation of norketobemidone from ketobemidone was studied and compared with the activities of 11 major CYP enzymes in human liver microsomes. The formation of norketobemidone from ketobemidone (1 microM) correlated best with CYP2C9 activity, measured as losartan oxidation (rs = 0.82, n = 19, p < 0.001), but there was also a strong correlation with CYP3A4 activity. Additionally, a good correlation was observed with CYP2C19, CYP2C8 and CYP2B6 at a ketobemidone concentration of 50 microM. Inhibition studies confirmed the involvement of CYP2C9 and CTP3A4 in the formation of norketobemidone. The formation rate of norketobemidone was three times higher in the CYP2C9*1*1 genotype group compared with the CYP2C9*1*2, CYP2C9*1*3 and CYP2C9*3*3 genotypes (p < 0.01). Treatment with verapamil as a PGP inhibitor did not affect the transport of ketobemidone in Caco-2 cells, indicating that PGP is not involved. The data suggest that CYP2C9 and CYP3A4 play a major role in the formation of norketobemidone at clinically relevant concentrations.

Cyclophosphamide induces mRNA, protein and enzyme activity of cytochrome P450 in rat.

The effects of cyclophosphamide (CPA) on CYP enzymes in vivo and its auto induction in rat were investigated in Wistar/Fu male rats at a single dose (40 or 200 mg kg(-1)) or as repeated dose of 200 mg kg(-1) CPA. After a single dose of CPA, mRNAs of CYPs 2B1, 2B2, 3A2, 2C11 were significantly induced up to 220-, 6.7-, 5.0- and 5.8-fold at the low dose CPA, and 4800-, 52-, 22- and 2.5-fold at the high dose. CYP2B1/2 and CYP3A proteins were increased by 4- and 2-fold (low dose) and by 28- and 1.7-fold (high dose). CYP2C11 protein levels were not altered. Microsomal activities of CYP2B, CYP3A and 2C11 were increased by 2-, 1.8- and 1.3-fold at low dose CPA, and 3.2-, 1.7- and 1.6-fold at high dose. A significant (p<0.05) decrease in CPA concentration and a significant (p<0.05) increase in 4-OH-CPA levels were observed with repeated administration of CPA. Acute induction effect on CYP2B1, 2B2, 2C11 and 3A2 and a substantial up regulation of CYP2B1 mRNA were observed after a single dose of CPA, auto induction was observed by repeated administration.

Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo.

The effect of cytochrome P450 (CYP) 2C9 polymorphisms on the stereoselective biotransformation of the oral anticoagulant phenprocoumon (PPC) to inactive, monohydroxylated metabolites was studied in vitro and in vivo. In human liver microsomes, the (S)-7-hydroxylation--being the major metabolic pathway--was significantly compromised in a gene-dose-dependent manner in samples expressing the CYP2C9*2 or CYP2C9*3 allele. The CYP2C9*3/*3 genotype corresponded to an almost fourfold lower (S)-7-hydroxylation rate than CYP2C9*1/*1 (wild-type). The intrinsic clearance of human recombinant CYP2C9*2 and CYP2C9*3 for the (S)-7-hydroxylation was 28.9 and 50.9% lower than of CYP2C9*1, respectively. The area under the plasma concentration-time curve (AUC) of PPC metabolites after oral intake of 12 mg racemic PPC was significantly lower in volunteers expressing the CYP2C9*2 or CYP2C9*3 allele. Increasing plasma AUC metabolic ratios (parent compound/metabolite) in CYP2C9*2 and CYP2C9*3 variant allele carriers were found for each hydroxylation reaction and the CYP2C9*3/*3 genotype corresponded to an about 10-fold higher metabolic ratio of PPC (S)-7-hydroxylation relative to CYP2C9*1/*1. CYP2C9 polymorphisms cause a markedly compromised PPC (S)-7-hydroxylation. However, PPC metabolism appears overall less influenced by CYP2C9 genotype compared with other oral anticoagulants and it may thus be a valuable alternative for therapeutic anticoagulation of patients expressing CYP2C9 variant alleles.

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation.

The role of polymorphic CYP2B6 in cyclophosphamide (CPA) bioactivation was investigated in human liver microsomes. A total of 67 human liver specimens were first genotyped with respect to the CYP2B6*5 and CYP2B6*6 variant alleles. CYP2B6 apoprotein levels in 55 liver microsomal preparations were assessed by immunoblotting. 4-Hydroxy-CPA and hydroxy-bupropion were quantified by using HPLC and LC-MS, respectively. 7-Ethoxy-4-trifluoromethyl coumarin O-deethylase activity was measured fluorometrically. The frequencies of CYP2B6*5 and CYP2B6*6 mutant alleles were 9.0 and 16.4%, respectively. CYP2B6 protein expression was detected in 80% of the samples, with a large variation (0.003-2.234, arbitrary units). There was a high correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation (n=55, r=0.81, P<0.0001). When based on the CYP2B6 apoprotein levels, the *6 carriers had significantly higher CPA 4-hydroxylation (P<0.05). CPA 4-hydroxylation also correlated significantly with other CYP2B6-specific reactions (n=20, P<0.0001). V(max) and K(m) for CPA 4-hydroxylation in recombinant CYP2B6 enzyme were 338 nmol/min/nmol enzyme and 1.4 mM, respectively. CYP2B6 showed much higher in vitro intrinsic clearance than previously observed in recombinant CYP2C19 and CYP2C9 variants in yeast expression system. Our results demonstrate that the polymorphic CYP2B6 is a major enzyme in the bioactivation of CPA. Moreover, we identified a strong impact of CYP2B6*6 on CPA 4-hydroxylation.

Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population.

AIMS: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect the therapeutic outcome during treatment with several drugs. The distribution of variant CYP2C9 alleles was therefore investigated in an Italian and an Ethiopian population. METHODS: Allele-specific PCR analysis was carried out in order to determine the frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 157 Italians and 150 Ethiopians. RESULTS: The frequencies of CYP2C9*1 (80%), CYP2C9*2 (11%) and CYP2C9*3 (9%) found in the Italian population were similar to other Caucasian groups. However in the Ethiopian population CYP2C9*1, CYP2C9*2 and CYP2C9*3 were present at a frequency of 94, 4 and 2% respectively. The 95% confidence intervals in CYP2C9*1, CYP2C9*2 and CYP2C9*3 between Italians and Ethiopians were 0.098, 0.176, 0.040, 0.098 and 0.040, 0.098, respectively. CONCLUSIONS: Our results indicate that the Ethiopian population has a unique relative distribution of the CYP2C9 alleles, which is not similar to any other ethnic group hitherto described.

Comparison of subretinal fluid levels of two 0.3% ciprofloxacin-containing eye drops.

PURPOSE: Two ophthalmic solutions of 0.3% ciprofloxacin eye drops are available in Turkey: Ciloxan and Siprogut. A previous study by the same authors was the first to report vitreous penetration of ciprofloxacin-containing eye drops. The aim of the present study was to compare the levels of drug found in the subretinal fluid by the two products following local administration. METHODS: Forty-three patients undergoing conventional retinal detachment surgery received either Ciloxan (22 patients) or Siprogut (21 patients). Beginning 6 h before surgery, two drops of solution were instilled onto the operative eye every 30 min for the first 3 h and then hourly for the next 3 h. Subretinal fluid samples were collected 30 min after administration of the last dose and were assayed for ciprofloxacin levels using a method involving high-performance liquid chromatography with fluorometric detection. RESULTS: The minimum and maximum subretinal fluid concentrations measured were 0.11 microg/mL and 0.65 microg/mL, respectively, with Ciloxan, and 0.08 microg/mL and 0.62 microg/mL, respectively wth Siprogut. There was no statistical difference between the subretinal fluid ciprofloxacin levels of the two products. The subretinal fluid drug evels attained by both products were below the minimum inhibitory concentrations of common ocular pathogens. CONCLUSIONS: Ciloxan and Siprogut can penetrate subretinal fluid. The ocular bioavailability of ciprofloxacin after local administration is equivalent for both pharmaceutical products.

The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro.

INTRODUCTION: The polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) catalyses the metabolism of many drugs including S-warfarin, acenocoumarol, phenytoin, tolbutamide, losartan and most of the non-steroidal anti-inflammatory drugs. Diclofenac is metabolised to 4'-hydroxy (OH), the major diclofenac metabolite, 3'-OH and 3'-OH-4'-methoxy metabolites by CYP2C9. The aim of the present study was to clarify the impact of the CYP2C9 polymorphism on the metabolism of diclofenac both in vivo and in vitro. SUBJECTS, MATERIALS AND METHODS: Twenty healthy volunteers with different CYP2C9 genotypes [i.e. CYP2C9*1/ *1 (n = 6), *1/*2 (n = 3), *1,/*3 (n = 5), *2/*3 (n = 4), *21*2 (n = 1), *31*3 (n = 1)] received a single 50-mg oral dose of diclofenac. Plasma pharmacokinetics [peak plasma concentration (Cmax), half-life (t 1/2) and area under the plasma concentration-time curve (AUCtotal)] and urinary recovery of diclofenac and its metabolites were compared between the genotypes. Diclofenac 4'-hydroxylation was also analysed in vitro in 16 different samples of genotyped [i.e. CYP2C9*1/*1 (n = 7), *1/*2 (n=2), *1/*3 (n = 2), *2/*3 (n = 2), *2/*2 (n = 2), *31/*3 (n = 1)] human liver microsomes. RESULTS: Within each genotype group, a high variability was observed in kinetic parameters for diclofenac and 4'-OH-diclofenac (6- and 20-fold, respectively). No significant differences were found between the different genotypes either in vivo or in human liver microsomes. No correlation was found between the plasma AUC ratio of diclofenac/4'-OH-diclofenac and that of losartan/ E-3174, previously determined in the same subjects. CONCLUSION: No relationship was found between the CYP2C9 genotype and the 4'-hydroxylation of diclofenac either in vivo or in vitro. This, together with the lack of correlation between losartan oxidation and diclofenac hydroxylation in vivo raises the question about the usefulness of diclofenac as a CYP2C9 probe.

Subretinal fluid levels of topical, oral, and combined administered ciprofloxacin in humans.

AIMS: To investigate the subretinal fluid (SRF) penetration of ciprofloxacin following topical, oral, and combined administration. METHODS: 34 patients undergoing conventional retinal reattachment surgery were randomly assigned to three groups. Twelve patients received topical ciprofloxacin, 11 patients received oral ciprofloxacin, and the other 11 patients received combined drug administration. SRF drug level was measured by using high performance liquid chromatography method. RESULTS: The highest drug concentrations of all tested modes were attained following combined administration and lowest following topical administration (p<0.001). The SRF drug concentration following oral administration was also significantly higher than that of topical administration (p<0.001). Concentrations after oral and combined administration did not differ significantly (p = 0.217). CONCLUSIONS: Topical ciprofloxacin can penetrate SRF. Ocular bioavailability of ciprofloxacin in SRF after oral and combined administration is equivalent.

Penetration of topical, oral, and combined administered ofloxacin into the subretinal fluid.

AIMS: To assess the subretinal fluid (SRF) levels of ofloxacin following topical, oral or combined administration. METHODS: 31 patients undergoing conventional retinal reattachment surgery were randomly assigned to three groups. Nine patients received topical ofloxacin, 11 patients received oral ofloxacin, and the other 11 patients received combined administration. Collected SRF samples were analysed for drug level by using high performance liquid chromatography. RESULTS: SRF drug levels after oral and combined administration were significantly higher than that after topical administration (p=0.0002 and p=0.0002, respectively) while there was no significant difference between oral and combined administration (p=0.0844). CONCLUSIONS: Ocular bioavailability of ofloxacin in SRF after oral and combined administration is equivalent. The addition of oral ofloxacin to topical therapy increased drug SRF penetration sixfold.

Penetration of ofloxacin and ciprofloxacin in aqueous humor after topical administration.

BACKGROUND AND OBJECTIVE: To compare the aqueous humor levels of 0.3% ofloxacin and 0.3% ciprofloxacin containing eyedrops in patients with healthy cornea. PATIENTS AND METHODS: Fifty patients with cataract were randomly assigned to have 0.3% ofloxacin containing eyedrop (25 patients) or 0.3% ciprofloxacin containing eyedrop (25 patients). Both drugs were repetitively instilled to each patient for 6 hours before the surgery. Aqueous samples were collected after penetrating the anterior chamber during cataract extraction and assayed by high-performance liquid chromatography method. RESULTS: The aqueous humor level of ofloxacin (1.43 +/- 0.26 microg/ml, mean +/- SEM) was significantly higher than that of ciprofloxacin (0.35 +/- 0.07 microg/ml) following the topical application (P < .0002). CONCLUSION: Aqueous humor penetration of topical ofloxacin is about 4 times higher than that of topical ciprofloxacin when the drugs are applied as described above.

Cyclosporine A preparations and their vehicles induce contraction of the guinea pig gallbladder in vitro: the role of cyclooxygenase metabolites.

The aim of this study was to establish whether prostanoids play a role in the contraction induced by cyclosporine A (CyA) preparations in the guinea pig isolated gallbladder strips. It was also aimed to study the effects of the preparations and their solvents on the acetylcholine-evoked rhythmic contractions of the guinea pig isolated sphincter of Oddi (SO). Isometric contractions were recorded. CyA parenteral and oral preparations and their vehicles, Cremophor-EL and Labrafil caused concentration-dependent and sustained contractions (74.2 +/- 6.2, 58.4 +/- 6.3, 88.9 +/- 4.9 and 47.5 +/- 6.2% of maximum KCl contraction, respectively) of gallbladder strips, but not of SO. Quinacrine, indometacin and ridogrel inhibited the contraction induced by CyA preparations and their vehicles in gallbladder strips (for CyA parenteral preparation, 34.7 +/- 6.7, 1.4 +/- 0.9, 19.0 +/- 6.4% of maximum KCl contraction, respectively). The drug and its vehicles changed neither the initial contraction nor the amplitude and frequency of the phasic contractions induced by acetylcholine in SO preparations. The results indicate that the drug is able to contract the gallbladder strips and the vehicles contribute to the contracting effect of CyA. Prostanoids may be responsible for the CyA-induced contraction of the gallbladder.

Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population.

Cytochrome P450 2C9 (CYP2C9) catalysis the metabolism of important drugs such as phenytoin, S-warfarin, tolbutamide, losartan, torasemide, and nonsteroidal anti-inflammatory drugs. A functional polymorphism of the CYP2C9 gene has been described. The variant alleles include CYP2C9*2 having a point mutation in exon 3 causing an Arg144Cys exchange, and CYP2C9*3 with a point mutation in exon 7 resulting in an Ile359Leu exchange. Genotyping of these variant forms was carried out in 430 Swedish healthy volunteers and three different methods were compared. Sequence analysis of the different PCR products revealed that other genes in the CYP2C locus were co-amplified in one of the methods applied, whereas the other two methods were specific for CYP2C9. The frequencies of the CYP2C9*1, CYP2C9*2 and CYP2C9*3 alleles in the population examined were found to be 0.819, 0.107, and 0.074, respectively. The need for careful evaluation of the genotyping procedure by sequence analysis of PCR products is emphasised.

Human aqueous and vitreous humour levels of ciprofloxacin following oral and topical administration.

PURPOSE: To assess aqueous and vitreous humour ciprofloxacin concentrations following oral and topical administration of ciprofloxacin in patients with non-inflamed cornea and an intact crystalline lens, and to compare the concentrations of the drug given by either route. METHODS: In this prospective study, 34 patients undergoing pars plana vitrectomy for various ocular pathologies were divided into two groups. Eighteen patients received 2 drops of 0.3% ophthalmic solution of ciprofloxacin every 30 min for 3 h and then every 60 min for the next 3 h, and 16 patients received a single oral dose of 1000 mg ciprofloxacin 6 h before surgery. The aqueous and vitreous humour samples were simultaneously harvested after oral or topical administration during pars plana vitrectomy to assess penetration of the drug. These samples were assayed for ciprofloxacin concentrations by a method described previously by us using high-performance liquid chromatography. RESULTS: The aqueous and vitreous humour levels of ciprofloxacin were 0.59 +/- 0.06 microgram/ml (mean +/- SEM) and 0.64 +/- 0.06 microgram/ml after oral and 0.44 +/- 0.07 microgram/ml and 0.22 +/- 0.04 microgram/ml after topical ciprofloxacin administration, respectively. Aqueous humour levels were not statistically significantly different following oral and topical administration (p = 0.069). However, the vitreous level of the drug after oral administration was significantly higher than that after topical administration (p < 0.001). CONCLUSION: Ocular bioavailability of ciprofloxacin in aqueous humour following oral and topical administration is found to be similar when the drug was applied as described above. Penetration of ciprofloxacin into vitreous humour is less than that into aqueous humour after topical administration.

Aqueous humour levels of topically applied ciprofloxacin and ofloxacin in the same subjects.

PURPOSE: To evaluate aqueous humour levels of topical 0.3% ciprofloxacin and 0.3% ofloxacin in the same subjects. METHODS: Thirty-two bilateral cataractous patients received topical 0.3% ciprofloxacin in one eye and 0.3% ofloxacin in the other eye before each cataract extraction. Eyedrops were repetitively instilled for 6 h. Aqueous humour samples were collected and assayed for drug concentrations by a method described originally by us using high-performance liquid chromatography. RESULTS: Mean aqueous ciprofloxacin and ofloxacin levels were 0.33 +/- 0.04 microgram/ml (mean +/- SEM) and 1.34 +/- 0.14 micrograms/ml respectively (p < 0.0001). CONCLUSION: Ofloxacin level in the aqueous humour is 4 times higher than that of ciprofloxacin in the same subjects.

Penetration of ofloxacin in human aqueous and vitreous humors following oral and topical administration.

PURPOSE: To determine aqueous and vitreous humor ofloxacin levels following oral and topical application of ofloxacin in patients with noninflamed cornea and intact crystalline lens, and to compare the drug levels provided by each route. MATERIALS AND METHODS: Twenty-six patients undergoing pars plana vitrectomy for various ocular pathologies were divided into two groups. Fourteen patients received two drops of 0.3% ophthalmic solution of ofloxacin every 30 minutes for 3 hours and every 60 minutes for the next 3 hours, and 12 patients received a single oral dose of 400 mg ofloxacin 8 hours before surgery. The aqueous and vitreous humor samples were simultaneously collected after oral or topical administration during pars plana vitrectomy to assess penetration of the drug. Samples were assayed for ofloxacin concentrations by a previously described method using high-performance liquid chromatography. RESULTS: The aqueous and vitreous humor levels of ofloxacin were 1.54 +/- 0.27 microg/mL (mean +/- standard error) and 1.77 +/- 0.24 microg/mL after oral and 1.44 +/- 0.24 microg/mL and 0.37 +/- 0.05 microg/mL after topical ofloxacin administration, respectively. Aqueous humor levels were not statistically different following oral or topical administration (P > 0.8). However, vitreous level of the drug after oral administration was significantly higher than that after topical administration (P < 0.001). CONCLUSION: Ocular bioavailability of ofloxacin in aqueous humor after oral and topical administration is similar when the drug is applied as described. Penetration of ofloxacin into vitreous humor is less than that into aqueous humor following topical application. The aqueous humor levels of ofloxacin via both routes and the vitreous level of the drug after oral route exceed the minimum inhibitory concentrations for certain bacterial species that frequently cause intraocular infection.