Jouko Savolainen

Prodrugs: design and clinical applications

Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5–7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

Large Neutral Amino Acid Transporter Enables Brain Drug Delivery via Prodrugs

The blood-brain barrier efficiently controls the entry of drug molecules into the brain. We describe a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific, large neutral amino acid transporter (LAT1) by conjugating a model compound to L-tyrosine. A hydrophilic drug, ketoprofen, that is not a substrate for LAT1 was chosen as a model compound. The mechanism and the kinetics of the brain uptake of the prodrug were determined with an in situ rat brain perfusion technique. The brain uptake of the prodrug was found to be concentration-dependent. In addition, a specific LAT1 inhibitor significantly decreased the brain uptake of the prodrug. Therefore, our results reveal for the first time that a drug-substrate conjugate is able to transport drugs into the brain via LAT1.

Paracetamol (acetaminophen) penetrates readily into the cerebrospinal fluid of children after intravenous administration

INTRODUCTION. The main action of paracetamol (acetaminophen) is presumed to be in the central nervous system. The central nervous system penetration of paracetamol has been described in children with intracranial pathologies but not in children with an intact blood-brain barrier. OBJECTIVE. We investigated the cerebrospinal fluid penetration of paracetamol in 32 healthy children, aged 3 months to 12 years, who were undergoing surgery in the lower body using spinal anesthesia. MATERIALS AND METHODS. In this open-label prospective study, children were given a single intravenous injection of paracetamol (15 mg/kg). Cerebrospinal fluid and venous blood samples were obtained between 5 minutes and 5 hours after injection. Paracetamol concentrations were determined from the cerebrospinal fluid and plasma by using a fluorescence polarization immunoassay. RESULTS. Paracetamol was detected in cerebrospinal fluid from the earliest sample at 5 minutes, although in this sample paracetamol concentration was below the limit of quantification of 1.0 mg/L. Subsequent paracetamol concentrations in cerebrospinal fluid ranged between 1.3 and 18 mg/L (median: 7.2 mg/L), plasma concentrations ranged between 2.4 and 33 mg/L, and cerebrospinal fluid/plasma ratios ranged between 0.06 and 2.0. The highest CSF paracetamol concentration was detected at 57 minutes. CONCLUSIONS. Paracetamol permeates readily into the cerebrospinal fluid of children. This fast and extensive transfer enables the rapid central analgesic and antipyretic action of intravenous paracetamol.

Co-Administration of a Water-Soluble Polymer Increases the Usefulness of Cyclodextrins in Solid Oral Dosage Forms

AbstractPurpose. The aim of this study was to investigate the effect of cyclodextrins (β-CD, HP-β-CD and (SBE)7m-β-CD), and co-administration of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs. Methods. Effects of cyclodextrins on the aqueous solubility of glibenclamide, with and without hydroxypropylmethylcellulose (HPMC), were determined by a phase-solubility method. Solid inclusion complexes were prepared by freeze-drying. Glibenclamide was administered orally and intravenously to beagle dogs. Results. Aqueous solubility of glibenclamide increased as a function of cyclodextrin concentration, showing an AL-type diagram for β-CD and an Ap-type diagrams for both of the β-CD derivatives studied. HPMC enhanced the solubilising effect of cyclodextrins, but did not affect the type of phase-solubility diagram. Orally administered glibenclamide and its physical mixture with HP-β-CD showed poor absolute bioavailability, while orally administered glibenclamide/cyclodextrin-complexes significantly enhanced the absolute bioavailability of glibenclamide. Orally administered glibenclamide/β-CD/HPMC and glibenclamide/(SBE)7m-β-CD/HPMC complexes showed similar absolute bioavailability compared to formulations not containing HPMC, even though 80% (in the case of (SBE)7m-β-CD) or 40% (in the case of β-CD) less cyclodextrin was used. Conclusions. The oral bioavailability of glibenclamide was significantly increased by cyclodextrin complexation. HPMC increased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significantly reduced by their co-administration. In conclusion, the pharmaceutical usefulness of cyclodextrins in oral administration may be substantially improved by co-administration of a water-soluble polymer.

Prodrug Approaches for CNS Delivery

Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug’s usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy.

Absorption Rate Limit Considerations for Oral Phosphate Prodrugs

AbstractPurpose. To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs. Methods. Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aqueous solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Additional absorption studies were carried out in rats. Results. Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 μM fosphenytoin, respectively. Hydrocortisones flux did not increase with hydrocortisone-phosphate at 100 μM. Permeability of the highly lipophilic and protein bound compound, DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was observed for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone solution, but the prodrug solution did yield higher entacapone plasma levels in rats when compared with an entacapone suspension. Conclusion. Ideal phosphate prodrug candidates are characterized by high permeability and low solubility (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.

Drug release from a porous ion-exchange membrane in vitro

The effect of environmental ionic strength on the rate of drug release from a cation exchange membrane was evaluated. Cationic propranolol-HCl, timolol, sotalol-HCl, atenolol and dexmedetomidine-HCl and neutral diazepam were adsorbed onto a porous poly(vinylidene fluoride) (PVDF) membrane that was grafted with bioadhesive poly(acrylic acid) chains (PAA-PVDF). Despite its porosity, the PAA-PVDF membrane acted as a cation exchange membrane. The release of adsorbed drug from the PAA-PVDF membrane was investigated by using a USP rotating basket apparatus. Adsorption of cationic drugs onto the PAA-PVDF membrane tended to increase with increasing lipophilicity of the drug. A decrease in the ionic strength of the adsorption medium increased the amount of the cationic drugs adsorbed onto the membrane, but had no effect on diazepam adsorption. The release of cationic drugs from the PAA-PVDF membrane was greatly affected by the ionic strength of both the adsorption medium and the dissolution medium, while ionic strengths did not affect diazepam release. Our results suggest that the ionic strength of both the adsorption and dissolution media substantially affects the release rate of a drug that has been adsorbed onto the ion exchange membrane, primarily via electrostatic interactions, while ionic strength has no effect on the release of a drug which has been adsorbed onto the membrane via non-electrostatic forces.

Cerebrospinal Fluid Distribution of Ibuprofen After Intravenous Administration in Children

BACKGROUND. Ibuprofen is the most commonly used nonsteroidal, antipyretic, antiinflammatory analgesic in children. Nonsteroidal, antipyretic, antiinflammatory analgesics act in both the peripheral tissues and the central nervous system. The central nervous system penetration of ibuprofen has been described in adults but not in children. OBJECTIVES. Our goals were to investigate the cerebrospinal fluid penetration of ibuprofen in children and evaluate the analgesic plasma concentration of ibuprofen after inguinal surgery in children. MATERIALS AND METHODS. A total 36 healthy children (25 boys) aged 3 months to 12 years received a single intravenous injection of ibuprofen (10 mg/kg). A paired cerebrospinal fluid and blood sample was obtained 10 minutes to 8 hours after the injection. In children having inguinal surgery, a second blood sample was obtained at the time that the child first had wound pain. RESULTS. The ibuprofen level was determined in all cerebrospinal fluid and plasma samples. Cerebrospinal fluid concentrations ranged between 15 and 541 μg/L, and the highest concentrations were measured 30 to 38 minutes after dosing. In all cerebrospinal fluid samples collected after 30 minutes, ibuprofen concentration exceeded that of unbound plasma. The plasma analgesic concentrations after inguinal surgery ranged between 10 and 25 mg/L. CONCLUSIONS. Ibuprofen penetrates the cerebrospinal fluid readily, with peak concentrations attained 30 to 40 minutes after intravenous injection of a 10 mg/kg dose. The plasma analgesic concentration after inguinal surgery with spinal anesthesia is 10 to 25 mg/L.

Synthesis and in vitro/in vivo evaluation of novel oral N-alkyl- and N,N-dialkyl-carbamate esters of entacapone.

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N-alkyl and N,N-dialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N-alkyl and N,N-dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t1/2 = 14.9-20.7 h), but hydrolyzed rapidly (t1/2 = 0.8-2.7 h) in human serum. However, in contrast to N-alkyl carbamates, N,N-dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N-Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N-alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.

Effects of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone

Entacapone is a new catechol‐O‐methyltransferase (COMT) inhibitor used clinically in a triple combination therapy for Parkinsons disease (PD). The bioavailability of entacapone after oral administration is low and subject to large interindividual variation. The purpose of this study was to evaluate aqueous solubility/dissolution profiles of entacapone in vitro, and to evaluate their role in the poor oral bioavailability of entacapone in rats. The effect of the novel pharmaceutical excipient hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) on the aqueous solubility and dissolution of entacapone, and on entacapone bioavailability in rats, was also studied.