title: Bioavailability of paracetamol with/without caffeine in Egyptian patients with hepatitis C virus.
abstract: OBJECTIVE
  This study investigates the involvement of liver dysfunction in the modulation of paracetamol pharmacokinetic profile in genotype-4 HCV patients treated with either paracetamol alone (Para) or in combination with caffeine (Para-Caf).
  
  
  METHODS
  Twenty healthy volunteers and 20 Child-Pugh B HCV patients, each divided into two equal subgroups, were examined, whose liver/kidney functions were correlated with their main clinical manifestation. After an overnight fasting, healthy and hepatic subjects received either a single dose of Para (1000 mg paracetamol) or Para-Caf (1000 mg paracetamol/130 mg caffeine). Two milliliters of saliva samples were collected prior to and at different time-intervals after drug administration and analyzed using HPLC.
  
  
  RESULTS
  There was a noticeable increase in the mean concentration time profile of salivary paracetamol concentrations in hepatic patients, with concomitant decrease in paracetamol clearance (CLT), along with induction in the primary pharmacokinetic (PK) parameters, C max, AUC(0-8 h) and AUC(0-∞) (by about 95, 82, and 64 %, respectively, after treatment with Para, and 98, 96, and 101 %, respectively, after treatment with Para-Caf), when compared with the corresponding parameters in healthy subjects. Additionally, the healthy subjects treated with Para-Caf exhibited bioinequivalent increase in C max, K a, and t 1/2 with decrease in T max when compared with the healthy individuals treated with Para alone. A similar pattern was recorded in hepatic patients after addition of caffeine to paracetamol, with even augmented significant increase in K a and t 1/2 (by 100 and 32 %, respectively).
  
  
  CONCLUSIONS
  Liver dysfunction modified the PK of paracetamol expressed as earlier effective paracetamol concentration, with obvious decrease in its clearance. Caffeine induced faster absorption (evidenced by shorter T max and higher K a) and prolonged t 1/2 of paracetamol, the effects that were more profound in hepatic patients. Further studies are needed to evaluate the influence of liver damage on paracetamol pharmacokinetics whenever repeated dosing is applied, to avoid possible drug accumulation.
authors.affiliation: Department of Pharmacology, Theodor Bilharz Research Institute, Warak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt. n.ellakkany@tbri.gov.eg.
authors.forename: Naglaa M
authors.identifier: http://orcid.org/0000-0002-5783-9945
authors.initials: NM
authors.lastname: El-Lakkany
authors.affiliation: Department of Pharmacology, Theodor Bilharz Research Institute, Warak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Hendawy
authors.affiliation: Department of Pharmacology, Theodor Bilharz Research Institute, Warak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt.
authors.forename: Sayed H
authors.initials: SH
authors.lastname: Seif El-Din
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr city, Cairo, Egypt.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Ashour
authors.affiliation: Department of Hepatogastroenterology, Theodor Bilharz Research Institute, Warak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt.
authors.forename: Raafat
authors.initials: R
authors.lastname: Atta
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr city, Cairo, Egypt.
authors.forename: Abdel-Aziz H
authors.initials: AA
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr city, Cairo, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Mansour
authors.affiliation: Department of Pharmacology, Theodor Bilharz Research Institute, Warak El-Hadar, Imbaba, P.O. Box 30, Giza, 12411, Egypt.
authors.forename: Sanaa S
authors.initials: SS
authors.lastname: Botros
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000700:Analgesics / Q000009:adverse effects / Q000493:pharmacokinetics; D018912:Arabs; D001682:Biological Availability; D002110:Caffeine / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012463:Saliva / Q000378:metabolism
chemical_list: D000700:Analgesics; D000082:Acetaminophen; D002110:Caffeine
keywords: Absorption rate constant; Bioavailability; Caffeine; Child-Pugh B HCV patients; HPLC; Paracetamol